More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
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Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
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IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\n
Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
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\n'}],latestNews:[{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"},{slug:"suf-and-intechopen-announce-collaboration-20200331",title:"SUF and IntechOpen Announce Collaboration"}]},book:{item:{type:"book",id:"101",leadTitle:null,fullTitle:"Laser Scanning, Theory and Applications",title:"Laser Scanning",subtitle:"Theory and Applications",reviewType:"peer-reviewed",abstract:"Ever since the invention of laser by Schawlow and Townes in 1958, various innovative ideas of laser-based applications emerge very year. 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\n\t\t\t
1. Introduction
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1.1. WRN is a RecQ helicase/exonuclease required for genome stability and to prevent premature ageing
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1.1.1. Clinical phenotype of Werner’s syndrome
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Humans possess five distinct RecQ helicases (see Figure 1), all of which possess a hallmark RecQ helicase domain. Mutation or loss in any one of three human RecQ helicases give rise to genetic instability syndromes: WRN mutation gives Werner’s syndrome (WS), BLM loss results in Bloom syndrome (BS), and Rothmund-Thomson syndrome (RTS) is caused by mutation of RECQL4[1] -. WRN has come to prominence because its loss of function results in human Werner’s syndrome, a segmental progeria (premature ageing) characterised by many signs and symptoms of normal ageing at both the organismal and cellular levels, with shortened lifespan (median age of death 47 years [2]). In particular WS patients suffer from osteoporosis, athero-and arterio-sclerosis and a high cancer incidence (particularly sarcoma) together with metabolic disorders normally associated with increased age, especially type II diabetes and lipodystrophy. Furthermore, patients show outwardly recognisable signs of ageing such as cataracts, greying hair and skin wrinkling, while female WS patients suffer premature menopause and both sexes show hypogonadism, with decreased fertility (reviewed in ref. [2]).
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1.2. Cellular phenotype on WRN loss
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This premature ageing phenotype is also observed at the cellular level: fibroblasts from WS patients undergo highly premature replicative senescence in culture, failing to proliferate after only 9-11 population doublings, compared with the 50-60 doublings characteristic of wild type fibroblasts [3]. Transcriptomic studies have demonstrated that >90% gene expression changes associated with normal ageing are seen in young WS cells [4], while glycosylation of blood albumin (a biomarker of ageing) in young WS patients is equivalent to levels detected in normal centenarians [5]. Importantly, loss of function of WRN is associated with significant genome instability with a high frequency of chromosomal translocations and deletions [6, 7], which is thought to contribute to the increased cancer risk. Genome instability is a hallmark of defective S phase checkpoint proteins (reviewed in ref. [8]), suggesting either than WRN is directly involved in the checkpoint, or that it normally serves downstream of the checkpoint such that its loss prevents correct execution of the arrest and recovery pathways. Notably, it is not only WS patients who are more susceptible to cancer on WRN loss: epigenetic inactivation by methylation of CpG islands in the WRN gene promoter has been reported in epithelial and mesenchymal cancers with value in prognosis in colorectal cancer [9], while specific WRN SNPs have been correlated with breast cancer incidence [10], even though such genetic changes do not alter the helicase or exonuclease activities of the protein or modulate the levels expressed. WRN is therefore of interest not only to those attempting to understand the molecular basis of human ageing, but also to cancer biologists – indeed WRN knockdown is likely to promote cancer cell death and hypersensitise cells to current chemotherapeutic agents such as camptothecin that impact on DNA replication [9, 11, 12]. Small molecules that specifically inhibit WRN but not other RecQ helicases are therefore likely to have therapeutic potential [13].
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1.3. WRN protein
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The wide range of ageing-associated phenotypes in WS patients and their cells indicates a fundamental role for WRN in preventing premature ageing, but how can loss of one protein lead to the pleiotropic outcomes of human ageing? The most important clue came from cloning the WRN gene [14], which showed for the first time that the human WRN gene encodes a large protein of 1432 amino acid (~162kDa) with an amino terminal exonuclease domain conserved with proteins of the DnaQ family, and a central helicase domain of the RecQ family. In addition, DNA binding (RQC) and protein interaction (HRDC) domains exist distal to the helicase domain (Figure 1A). Immunofluorescence and mutational studies have demonstrated that WRN is a nuclear protein with both NLS and NoLS sequences situated at the C terminus [15]), that appears to be sequestered in the nucleolus [16] except during S phase or upon DNA damage, when it is redistributed to sites of DNA replication or repair ([17-19].
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Of the five human RecQ proteins, WRN is the only one to possess exonuclease activity [20]. Acting in a 3’-5’ direction (as shown using 3’- or 5’-end labelled substrates), WRN exonuclease has been demonstrated to bind onto overhanging 5’ ends of the guide strand of duplex DNA and cleave the target strand sequentially, though with relatively low processivity [21]. While it cannot cleave blunt ended substrates, nor those where ends are blocked by bulky lesions [22], WRN exonuclease degrades substrates that are likely to be found both during DNA repair and as intermediates in DNA replication, including forks and bubble substrates [23] (see Table 1). Despite early reports of lack of activity on short single-stranded DNA (e.g. [21]), WRN exonuclease can digest single stranded oligonucleotides over 50 bases in length [24, 25].
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Figure 1.
The RecQ helicase family. (A) Domain organization of human WRN. Note that for human WRN, the RQC serves in DNA binding and the HRDC is probably involved in protein-protein interaction, though these roles may be reversed in other RecQs. (B) Humans have 5 RecQ helicases (boxed), named after the archetypal RecQ of E. coli. Human WRN is unique in the family in possessing an exonuclease domain. In invertebrates such as Drosophila and C. elegans, the exonuclease (red) and helicase (blue) activities are encoded by separate genes.
Substrates unwound by WRN helicase or degraded by WRN exonuclease. (Note that BLM also unwinds the same substrates as WRN helicase)
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The helicase activity of WRN is highly conserved with other RecQ helicase family members, acting 3’-5’to unwind duplex DNA in an ATP-dependent manner [26]. Within the helicase domain are seven conserved motifs characteristic of the RecQ family. In general, RecQ helicases are adept at unwinding unusual DNA structures that can inhibit the course of normal DNA replication. Examples are tailed and forked duplexes, small gaps and flaps (commonly found as DNA repair and recombination intermediates), bubble substrates and displacement-loop triplex and Holliday junctions (common at telomeres and during recombinational repair and sister chromatid exchange), and G-quadruplexes which are often found at tracts rich in guanine such as at the telomere (e.g. [27], reviewed in ref. [28], see Table 1). It is important to note that the helicase and exonuclease activities do not simply act as independent entities in cells, but that their actions are almost certainly co-ordinated and interlinked. For example, co-operation between them is required during telomere maintenance ([29]; see section 4 below for more detail).
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WRN helicase template specificity requires DNA binding that is probably mediated through the conserved RQC domain. X-ray crystallographic analysis has shown some unusual features, in that binding of WRN to DNA does not occur through a standard ‘recognition helix’, but instead through a beta wing of the RQC domain that inserts like a wedge between the terminal bases of blunt duplex DNA to unwind one base even in the absence of ATP [30]. How this binding correlates with WRN’s lack of unwinding of blunt ended substrates remains to be determined. In addition to binding to DNA, WRN binds to many different proteins at the replication fork, the telomere and during fork recovery after stalling. Protein interaction with WRN may occur through the helicase-and-ribonuclease D/C-terminal (HRDC) domain; while this region is through to be important for DNA binding in E. coli RecQ and yeast Sgs1, the conserved for DNA interaction surface is lacking in human WRN, and the domain is unable to bind DNA in vitro, but that reveals many exposed alpha helicases that are likely to bind to protein partners [31].
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1.4. WRN orthologues
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While the exonuclease and helicase activities are both encoded by the same gene in vertebrates, giving rise to one multifunctional protein, the enzymes are encoded by separate genetic loci in plants, invertebrates and prokaryotes (Figure 1B, reviewed in ref. [32]), with physical and/or functional interaction between the helicase and nuclease proposed in vivo. (Figure 1, reviewed in ref. [32, 33] For example, in the fruit fly Drosophila melanogaster, we have cloned and characterised the orthologue of human WRN exonuclease encoded by the fly locus CG7670 [34]. Drosophila WRN exonuclease (DmWRNexo) is a 3’-5’ exonuclease [35] that shows remarkable substrate conservation with human WRN exonuclease and utilises conserved residues at the active site for nucleic acid cleavage [36]. Flies homozygous for a strong hypomorphic mutation in CG7670 have greatly elevated levels of recombination that appears to occur through reciprocal exchange, and are hypersensitive to the topoisomerase poison camptothecin, that leads to replication fork collapse [37]. Hence loss of only the WRN exonuclease activity in flies results in many features characteristic of human WS, suggesting a key role for the exonuclease in preventing premature ageing. We consider the possible role(s) of WRN exonuclease in replication fidelity, restart of stalled forks and telomere maintenance in more detail below (see sections 2.2, 3.4 and 4 below).
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A limitation to studying WRN in flies is the lack of a fully characterised WRN helicase orthologue. However, the nematode worm C. elegans has a highly conserved WRN-like helicase, encoded by the wrn-1 gene, and two candidate exonucleases, at loci ZK1098.8 (mut-7 [38]) and adjacent ZK1098.3. RNAi knockdown of wrn-1 results in shortened lifespan [39] and perturbation of the S phase checkpoint via ATM/R kinases [40], suggesting both that WRN is important during DNA replication, and that its role is critical in maintaining normal longevity of the organism. These outcomes are of particular interest since they so closely echo the findings in humans, but in a genetically tractable and short-lived lower eukaryotic model organism. In plants, WRN has been most studied in Arabidopsis, where physical and function interaction has been described between the exonuclease (AtWEX) and helicase (AtWRN) orthologues [41]. In budding yeast and fission yeast, there is only one RecQ helicase (Sgs1 and Rqh1, respectively); whether these proteins interacts directly with an exonuclease to reconstitute human WRN-like activity is yet to be determined, though genetic interaction between Rqh1 and Mus81/Eme1 has been reported [42].
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Because of the phenotypes resulting from WRN loss or mutation, it has been implicated in many aspects of DNA metabolism, including transcription, DNA repair, recombination and telomere maintenance. Its role in DNA replication will be discussed in this chapter, including not only a direct role in normal processive DNA replication, and replication of the telomeres, but also in preventing replication fork stalling or assisting fork recovery after arrest.
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1.5. S phase defects in WS cells
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Fibroblasts and lymphoblastoid cells from Werner’s syndrome patients show a defect in progression through S phase [17, 43]. FACS analysis demonstrates both a longer duration of S phase and an overall significant increase in cell cycle time in primary fibroblasts from WS patients ([17] and in normal primary fibroblasts in which WRN was depleted by shRNAi by 80-90% [44]. Early studies on replication rates in WS fibroblasts used alkaline sucrose gradients to detect the size of nascent DNA, demonstrating slower replication in WS cells compared with normal controls [45]. The ability of WS cells to incorporate Texas-red-dUTP into nascent DNA is also significantly impaired [46]. Interestingly, while acute shRNAi-mediated WRN depletion in SV40 T antigen-transformed cells had no impact on cell cycle progression in the absence of imposed replication stress, primary fibroblasts depleted of WRN did show an S phase delay [44]. Hence it appears that loss of WRN protein results in an S phase phenotype.
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WRN has been isolated within a large multi-protein replication complex [47]and found to interact in vitro with purified PCNA. The binding region has been localised to a PIP-like motif on WRN towards the amino terminus [18], which is likely to bind within the hydrophobic pocket of PCNA, as described for other PIP-containing proteins (see section 2.1). Studies on Xenopus egg cell-free extracts depleted of the frog orthologue of WRN, called FFA-1 (focus-forming activity-1) initially suggested that the protein was required for establishment of replication foci and thus served a central role in DNA synthesis [48]. (Note however that immunoprecipitation from Xenopus egg extracts is fraught with difficulties and accidental removal of other components such as membranes may inadvertently lead to loss of replication capacity). Subsequently, FFA-1 was shown to localise to sites of DNA synthesis coincident with RPA, and expression of a dominant negative GST-FFA-1 fusion protein blocked replication activity [49]. Similar immunofluorescence studies in both HeLa cells and primary human fibroblasts, supported by high-resolution immuno-electron microscopy, also showed WRN present at a subset (~60%) of replication foci, colocalising with PCNA [18]. This localisation is in the absence of replication stress, while on HU arrest, the majority of WRN relocates from the nucleolus to RPA-containing foci that are suggested to represent stalled forks [19]. Hence WRN is present at replication sites, and in its absence, cell cycle and DNA synthesis phenotypes are consistent with a replication defect.
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2. WRN at the replication fork
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In order to appreciate where WRN acts during DNA replication, it is necessary to understand the core structure of the DNA replication fork during the elongation stage of DNA replication. During elongation, processive polymerisation of the leading strand is carried out by DNA polymerase epsilon (pol ε) and the leading strand by DNA polymerase delta (pol δ) (based on mutational studies of the proof-reading domains of each in yeast) [50-52]. The replicative polymerases are tethered to the template by association with the homotrimeric sliding clamp protein PCNA (proliferating cell nuclear antigen) [53]. Co-ordination between leading and lagging strands may be achieved through the action of the GINS/Cdc45 complex that has been proposed to act as a replisome progression complex (RPC) [54]. On the lagging strand, repeated cycles of priming by DNA pol α-primase results in synthesis of 7-10 nucleotide of RNA primer followed by ~20 nucleotides of initiator DNA (with error rates of 10-2 and 10-4 respectively), followed by switching to the higher fidelity and more processive DNA pol δ on the lagging strand and pol ε on the leading strand. This switch occurs through a multistep loading process essentially requiring recognition of the primer-template junction (where RPA is bound to the unwound single-stranded parental DNA) by RFC, an AAA+ ATPase that serves to load the sliding clamp PCNA. Pol δ is then recruited to PCNA through its p66 subunit to synthesise approximately 200 nucleotides of the Okazaki fragment. (For a more detailed discussion of fork establishment, see ref. [55]).
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2.1. Okazaki fragment processing
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Because of the low fidelity of pol α-primase, it is essential to remove both the RNA primer and iDNA during Okazaki fragment processing (OFP) This is coincident with continued synthesis of nascent DNA on the lagging strand; processive replication by pol δ results in displacement of the RNA-iDNA primer as a 5’ flap and its removal by one of a range of postulated pathways involving RNase H1, FEN1, Dna2 (on long RPA-coated flaps) and other helicases/nucleases including Pif1 and possibly a RecQ helicase (Sgs1 in yeast, WRN in humans) (reviewed in ref. [56]). Pol δ synthesises DNA to fill the gap and DNA ligase seals the nick in the phosphodiester backbone. These steps in Okazaki fragment processing (OFP) may be co-ordinated through differential binding of the separate enzymes to PCNA, which has been suggested to act as a molecular ‘toolbelt’ in OFP [57]. Association of the OFP proteins[1] - with PCNA occurs through a conserved PCNA-interacting peptide (PIP) of the general motif QxxL/M/IxxFF to the hydrophobic pocket of PCNA formed at the interdomain connector loop (e.g. [58, 60], reviewed in ref. [61]). Each PIP is likely to bind by an induced fit mechanism, since the crystal structures of PCNA bound by its various partners shows variation in this loop region [62]. Notably, WRN has a conserved PIP, and peptide ELISA studies showed that this region is sufficient for PCNA binding in vitro [18]. Additionally, WRN binds to and stimulates the nuclease activity of Fen1, which may contribute to efficiency of Okazaki fragment processing [63]; as WRN binds to Fen1 immediately adjacent to its PCNA binding site, it is likely that there is some interplay between the three proteins [64] that may be important in Okazaki fragment processing, though this has not been fully explored.
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2.2. Proof-reading during processive DNA synthesis
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DNA replication overall has an extremely low error rate of 10-9, achieved in part by the very high fidelity of the processive replicative polymerase ε and δ, and also by additional ‘extrinsic’ proofreading activities together with mismatch repair (MMR) to remove incorrectly incorporated bases. The high fidelity DNA polymerases ε and δ achieve an error rate of ~2 x10-5 (reviewed in ref. [65]) through two key structural features. Firstly, the active site is only fully formed upon acceptance of the correct incoming dNTP to create a solvent–inaccessible site that is partially specified by correct helical geometry of duplex DNA, thus increasing enthalpy and decreasing entropy for correct nucleotides and allowing high discrimination over incorrect nucleotides. Secondly, these polymerases each possesses a 3’-5’ exonuclease active site whereby the nascent DNA swings through ~40o to present to this site [66], and where incorrect nucleotides are removed by hydrolysis of the phosphodiester backbone just created. X-ray crystal structures of the isolated WRN exonuclease domain have shown that WRN shares structural homology with exonuclease domains of the high fidelity DnaQ family of replication polymerases, suggesting a possible role for WRN in editing DNA, either during DNA synthesis or in processing free ends, in collaboration with and stimulated by the end-binding protein Ku [67]. Very recently, it has been shown that WRN assists pol δ (possibly on the lagging strand during Okazaki fragment synthesis) by removing 3’ mismatches, thus allowing the polymerase to extend primers [68]. This supports a direct role for WRN in Okazaki fragment synthesis.
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3. Replication fork stalling – the role of WRN
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3.1. High rates of replication fork stalling in WS
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Early electron microscopy studies of 3H-T labelled DNA in fibre autoradiographs suggested a problem with replication origin spacing in WS [69, 70], though subsequent higher resolution studies using fluorescent antibodies to halogenated nucleotides suggest rather that it is replication fork rate, not inter-origin distance, which is abnormal in WS cells [17, 44]. Indeed, these DNA combing studies, that analyse individual DNA molecules labelled during replication, have demonstrated a problem with replication fork progression in WS cells, resulting in a high degree of replication fork asymmetry from what should be bidirectional origins [17]. Such studies led to the proposal that replication forks stall at high frequency in cells lacking WRN protein. Why should WS cells be particularly prone to fork stalling?
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3.2. Causes of fork stalling
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The replication fork encounters barriers during normal replication, such as unusual DNA structures arising at G-rich regions (G4-quadruplex) or fragile sites. These structures must be unwound to present a single stranded template suitable for copying; a high incidence of replication fork stalling is likely if the normal mechanisms for tackling the unusual structures is lacking. Alteration in nucleotide pools through treatment with hydroxyurea (HU), or polymerase inhibition with the dCTP mimic aphidicolin results in replication fork arrest in the absence of template abnormalities or lesions. In addition, exogenous agents can cause formation of lesions in the DNA that the replication fork cannot easily pass over – for example, methylated or oxidized bases.
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Replication fork pausing or stalling is therefore likely to be a common occurrence, and the cell has mechanisms to stabilise the fork, deal with the unusual structure or repair the damaged region, and allow fork restart. Where DNA synthesis pauses but the MCM replicative helicases proceed to unwind the duplex template, regions of single stranded parental DNA arise, that are rapidly coated with RPA. This forms a signal to the S phase checkpoint machinery, particularly the kinase ATR, that, together with other checkpoint kinases such as Mec1, Chk1 and Chk2 (Rad53) and mediator Mrc1, leads both to recruitment of proteins to deal with the particular fork progression barrier, and to stabilisation of the replisome at the stalled fork, reviewed in ref. [8]. Indeed, DNA pol ε has been shown to stay associated with stalled forks in yeast [71] under the influence of Rad53 signalling. Replication fork restart then occurs once the damage has been resolved and the checkpoint lifted. More serious to the cell is the collapse of replication forks as they traverse regions of the template containing single strand breaks – single-stranded breaks are converted to double-strand breaks (DSBs) by the passage of the replication fork, forming highly cytotoxic and potentially recombinogenic lesions. Hence surveillance and rescue mechanisms must exist in the cell to deal both with stalled and collapsed forks. The RecQ helicase family has been implicated as key in this mechanism.
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3.3. Dealing with unusual structures before they arrest the fork
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The most efficient mode of replication involves the removal of barriers to fork progression before they lead to fork stalling. Importantly, WRN has been shown to be required by DNA pol δ (but not α or ε) to unwind G4 DNA [72], bubbles and D loops [68] to allow pol δ-mediated synthesis over such template sequences without leading to fork stalling. In addition, the helicase activity of WRN is also required to limit the formation of single stranded DNA regions and gaps during replication of common fragile sites (CFS) [73, 74] and enhances processivity of DNA pol δ on fragile site FRA16D over hairpins and microsatellite regions, requiring either the helicase or DNA binding activities of WRN [75]. Hence one important role of WRN in DNA replication is to present the replisome with a template that is easy to replicate, but does it act at any other point to ensure efficient replication?
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3.4. Is WRN involved in fork restart or progression following restart?
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Where replication forks have stalled, replication restart can occur in one of a number of ways: (i) the block may be repaired (or removed); (ii) it may be bypassed using error-prone translesional synthesis (TLS), or (iii) it may be avoided by using an alternative template (e.g. the newly synthesised region on the opposite strand, resulting from fork regression or generated by recombination). The first option is usually the easiest and the least likely to have mutational consequences; translesional synthesis is inherently more likely to cause mutation (pol iota (ι), for example, has an error rate of 0.72 i.e. it incorporates nucleotides almost at random, irrespective of the template sequence [76, 77]), whilst recombination requires a suitable donor template that is not always available. The type of lesion, whether it is on the leading or lagging strand, and the surrounding environment all contribute to how the replication block is dealt with. For example, nucleotide depletion following HU treatment imposes replication stress and can lead to fork stalling, but such stalling may be ‘seen’ differently by the checkpoint and restart machinery to forks that stall at physical barriers caused by damaging agents such as MMS.
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It appears that RecQ helicases may aid in pathway ‘choice’, although the mechanisms that dictate which pathway is utilised are not fully understood. For instance, yeast complementation studies in rad50 mutants have demonstrated that BLM is important in resistance to ionising radiation that causes double-strand breaks [78], while WRN confers resistance to drugs such as MMS that lead to replication fork stalling [79, 80]. In human cells, dual labelling of DNA before and after either HU or MMS treatment and analysis by fibre spreading (DNA combing) has shown that cells acutely depleted of WRN using shRNAi were still able to preserve replisome integrity upon HU- or MMS-induced fork stalling, though following recovery, replication fork rates were slower in WRN-depleted cells than controls, as evidenced by much shorter tracts of labelled DNA post-treatment compared with those synthesised before treatment [44]. It has been proposed [44] that WRN leads to rapid elimination of single-stranded DNA tracts by promoting recombination (using the sister chromatid as template), by enhancing translesion polymerase-mediated gap filling, or by removing DNA immediately after fork passage. It has therefore been suggested that the genome instability in WS results from a defective response to stalled replication forks.
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3.5. Error-prone translesional synthesis to relieve the replication block
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Some lesions such as those caused by MMS or 4NQO present an insurmountable barrier to templating for the high fidelity B family DNA polymerases, but error-prone replication through these small lesions is often less costly for the cell than replication pausing and recruitment of repair complexes. Such error-prone synthesis is conducted by the Y family translesion DNA polymerases (TLS pols). These can pair nucleotides opposite modified and unusual bases, but at the cost of fidelity (ranging from error rates of ~6 x 10-3 for pol kappa (κ), through 3.5 x 10-2 for pol eta (η) to the essentially random 0.72 error rate for pol ι [76, 77, 81, 82]). The active site of such polymerasis is much larger than that of the proofreading polymerasis, allowing for unusual base pairing geometry, helical distortion of the template DNA, and solvent access [83]. Consistent with an important role for WRN in replication fork progression after pausing, WRN has been found to promote the processivity of Y-family TLS pols on a wide range of substrates including oxidized bases, abasic sites, and thymine dimers [84]. This activity is specific to WRN, and appears to increase the apparent Vmax of polymerisation. This does not require either catalytic activity of WRN, as proteins with point mutations that ablate both helicase and exonuclease activities can still promote pol η polymerisation, although neither catalytically-active BLM nor RecQ5 can substitute [84].
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3.6. WRN suppresses illegitimate recombination at stalled forks
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Whilst the experiments described above strongly support the assertion that WRN is required for fork progression after restart, others have suggested that WRN is itself required to promote restart, possibly through preventing either the accumulation of recombinogenic substrates or in suppressing recombination itself. High levels of spontaneous Rad51 foci in WS cells indicate the presence of an increased number of DNA double-strand breaks (DSBs) and elevated recombination when WRN is absent, supporting the assertion that WRN blocks excessive and illegitimate recombination. Indeed, stalled forks are thought to regress to ‘chicken foot; structures with 4-way Holiday junctions that can either be removed by exonuclease degradation of the free ends, by branch migration to a point at which replication can simply restart, or by recombination at the junction (see Figure 2). WRN is likely to suppress the recombinational route, as shown by partial complementation of yeast cells defective in Sgs1 by expression of human WRN. Accumulation and persistence of Holliday junctions is likely, since ectopic expression of the bacterial RusA resolvase allows WS cells to proliferate as rapidly as control cells, and to resist treatment with CPT or 4NQO (fork collapse and fork stalling agents) to which WS are normally hypersensitive [46].
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WRN helicase may branch migrate the chicken foot to ‘fold back’ the regressed form and thus re-establish a normal fork structure (Figure 2). Indeed, fork regression by WRN on RPA-coated DNA has recently been reported [85]. Alternatively, WRN exonuclease may degrade regions of the chicken foot and allow reformation of a normal replication fork. In addition to its own exonuclease activity, WRN associates with human Exonuclease 1 (Exo1), stimulating its activity [86]. It may therefore be the case that the two nuclease activities combine to remove regressed forks. It has been suggested that in the absence of WRN, the recombinational route is used to process the accumulated HJs, and that this requires the action of the nuclease Mus81; fission yeast Rqh1 suppresses Mus81 mutation [42] and human WRN suppresses Mus81-mediated recombination [87].
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Figure 2.
Possible roles of WRN in replication restart after fork stalling (see text for details)
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3.7. Template switching at stalled forks
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Leading strand blockage often uncouples the replicative helicases from the rest of the replisome, allowing significant unwinding to form long tracts of single-stranded DNA, with lagging strand synthesis continuing for a distance [88]. The accumulated long single stranded loop of leading strand DNA is highly susceptible to damage. Replication fork restart on the leading strand might simply utilise new priming by RPA-mediated recruitment of pol α-primase to the region of transition between singe stranded and duplex DNA (i.e. where the previous polymerase ceased synthesis), in much the same way that it normally reassociates with the primer-template junction in Okazaki fragment synthesis. Alternatively, regression of the replication fork may permit annealing to the new lagging strand using ‘template switching’ to give a Holliday junction that can then be reversed past the lesion [89, 90]. In bacteria, this can be done by RecQ helicase, with RecJ exonuclease to remove the protruding lagging strand flap [91].
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In mammals this is likely to require WRN and the flap endonuclease activity of FEN-1 [92]. WRN (and BLM) can induce fork regression over the lesion by local unwinding, and can lead to the formation of the chicken-foot. WRN can also reverse a regressed fork. Both BLM and WRN helicase activities can also catalyse branch migration of the DNA leading to recovery of the template daughter strand annealing via Rad51 [93], formation of a double Holliday junction and strand exchange. If the product here is a hemicatenenes, it can be resolved into either a chicken foot or a HJ and processed the same way. Ultimately, functional replication forks may be reformed [94]. Alternatively, the Holliday junction can then be cleaved by a resolvase and DSB repair as before. See Figure 2 (above) for a schematic of replication fork restart.
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3.8. How is WRN recruited to stalled forks?
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Stalling of replication forks initiates the caffeine-sensitive S phase checkpoint, mediated by RPA, ATR and Rad53. WRN recruitment to, or retention at, stalled forks may be direct through binding to RPA [85], but it also appears to require phosphorylation by the checkpoint kinase ATR [95]. When such phosphorylation is prevented, WRN cannot accumulate at repair sites and DNA strand breaks are detected [73]. That WRN is an in vivo as well as in vitro target of ATR has been confirmed by phosphoproteomic studies [96]. However, it is still the subject of research and debate as to whether WRN is an upstream sensor or downstream effector in the S phase checkpoint that responds to replication stress or stalled forks. For example, shRNAi-mediated WRN knockdown abrogated the S phase checkpoint on CPT treatment but did not affect checkpoint induction on HU exposure [97], suggesting that WRN may be an important ‘sensor’ of collapsed but not stalled forks, although the mechanism has yet to been defined. Perhaps fork collapse (e.g. upon CPT treatment) requires ATM, with its double-strand break sensing activity through recruitment by Ku and activation by DNA-PKcs (DNA-dependent protein kinase catalytic subunit), while fork stalling (e.g. on HU) uses the ATR pathway. This is consistent with differential regulation of WRN by the two kinases [73], and with a requirement for WRN not only in replication fork progression after stalling (see above) but also in directing recombination in concert with RAD51 and RAD54 [93]. Recently, it has been shown that WRN also interacts with the repair sliding clamp 9-1-1 (homologous structurally and functionally to PCNA, though acting in repair rather than replication), and that upon fork arrest, the 9-1-1 complex recruits TopBP1 that in turn recruits ATR which phosphorylates WRN [98]. Perhaps the initial type of damage that leads to fork arrest is therefore a deciding factor in the pathways of WRN recruitment and post-translational modification.
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3.9. Role of WRN at stalled forks on the lagging strand
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Lagging strand blocks do not uncouple the replication fork; rather, lagging strand polymerase merely stutters to the next primer to restart synthesis of the next Okazaki fragment [99, 100]. The resulting single-stranded gap is repaired by translesional synthesis as above (which may be error-prone) or by homologous recombination with the sister chromatid (which is more likely to retain fidelity). In E. coli, this requires formation of a double Holliday junction and resolution via non-crossover [101]. In mammals, BLM has the ability to mobilise double Holliday junctions and the resulting catenated DNA is resolved by topoisomerase III without crossover [102]. WRN does not interact with TopoIII and cannot migrate a double Holliday junction [103], although structures involved in intermediate formation (D-loops, G-quadruplex) might require either WRN or BLM. WRN can process a mobile D-loop [104] using the co-ordinate action of both helicase and exonuclease.
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However, WRN is also linked to the functionality of the lagging strand polymerase, pol δ. WRN stimulates the base incorporation of pol δ (but not α or ε) even in the absence of PCNA [105]. Pol δ is slowed at fragile sites and repetitive runs likely to cause hairpin or bubble structures, but this can be alleviated by the helicase functionality of WRN [75]. Like WRN, pol δ has a 3’-5’ exonuclease capability which it can use to proofread bases after insertion [106]. WRN can substitute at this proofreader, and cells with low levels of WRN show increased mutation of the lagging strand [107]. Interestingly, the exonuclease activity of pol δ is active on WRN-preferred DNA substrates such as Holliday junctions, D-loops and bubble duplex, and can form a complex with WRN [107] that increases the degradation of these substrates. WRN exonuclease is blocked by many common lesions [22, 108]; it will be interesting to find out whether the nuclease activity of pol δ is complementary to this, and might suggest why the two would functionally substitute within the lagging strand complex.
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Ultimately, fork restart requires proximal repositioning of the replication complex; this remodelling may make use of WRN nuclease activities to further process DNA ends and allow removal of damage. Interactions with PCNA and either strict (pol δ, pol α) or promiscuous (TLS pathway) repair polymerases and FEN1 flap removal activity can allow bypass of nicks and modified DNA bases at the same time as restart positioning, allowing many lesions to be handled.
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4. Involvement of WRN in telomere maintenance
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4.1. Telomere structure and replication
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Mammalian telomeres consist of a few kilobases of repetitive non-coding G-rich sequence (the human sequence is (TTAGGG)n) which must be ‘capped’ rather like a bootlace in order to stop the DNA end being recognised as a DSB via p53/p21 signalling [109] and instigating profligate double-strand break (DSB) repair [110]. Functional capping forms a lasso-like structure [111] called the telomere-loop (T-loop) where the repetitive telomere sequence folds back upon itself to displace a short segment of proximal sequence with a 3’ single stranded end to give a displacement-loop (the D-loop)[112]. The proteins that make up the telosome (or core shelterin complex [112]) include TRF1 and TRF2 [113], which bind and stabilise telomeric duplex DNA at the T-loop [114], and POT1 [115], a DNA-binding protein which coats and protects the tracts of single stranded telomeric sequence that occur at the telomeric D-loop and during telomeric replication and processing. Figure 3 shows the T and D loop structure with associated proteins.
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Telomeres are replicated by passage of a replication fork that initiated upstream of the chromosome end: obviously it is not possible to load the replisome or prime DNA synthesis beyond the end of the chromosome. At each round of replication, the telomeric sequence is unwound from the D (and possibly also the T) loops, and passively replicated by an incoming fork. While early reports suggested that priming on the lagging strand was defective at the very end of the chromosome, it has become apparent that both leading and lagging strands are normally replicated but that regeneration of a 3’ overhang for strand invasion to form the D loop involves end resection of the leading strand, thus removing sequence information and shortening the telomere at each round of replication.
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4.2. Telomere shortening leads to replicative senescence and genome instability
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Telomere shortening acts as a counting mechanism to indicate the number of cell divisions a somatic cell has passed through, and normal fibroblasts generally arrest at the Hayflick limit of 55-60 population doublings [3] under the influence of this telomere attrition. Hence cellular ageing is in a large part caused by progressive telomere loss – cells that lose telomeres more rapidly senesce more quickly that those with long telomeres, and people with prematurely short telomeres (e.g. mothers of chronically sick children[116], carers of partners with dementia and low paid workers experiencing
\n\t\t\t\t\n\t\t\t\twork-related stress) age prematurely [117, 118]. (Note that this is not the case in mice, where lab strains have extremely long telomeres and cells senesce prior to telomeres reaching a critical length). \n\t\t\t\t
To overcome this cellular ageing, it is vital that immortal cells such as those of the germline have a mechanism to restore telomeric DNA at every round of replication. Such cells express active telomerase, a reverse transcriptase which utilises its endogenous RNA template to regenerate telomeric sequence [119], but telomerase levels are extremely low or absent in most somatic cells [120]. Notably, immortalisation of cancer cells is accompanied by re-expression of telomerase [121] in about 85% of all human cancers, while the remaining 15% are able to maintain their telomere lengths in the absence of telomerase, by alternatives mechanisms, reviewed in ref. [122] (see section 4.6).
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Figure 3.
The structure of the telomere, showing the large telomere (T) loop and the smaller displacement (D) loop. Proteins TRF1, TRF2 and POT1 are critically important in stabilising the telomeric structure. WRN binds to all of these proteins
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Dysfunctional telomeres that become uncapped are liable to degradation or immediate repair by homologous recombination (HR) or non-homologous end-joining (NHEJ), the latter causing chromosome fusions that are usually catastrophic for the cell. However, the tightly capped telomere cannot serve as a template during replication, so regulated disassembly of the shelterin complex and unwinding of the D (and possibly T) loop is necessary for efficient copying of telomeric regions. The transient uncapping that occurs during replication is recognised by repair proteins as DNA damage [123], and the correct reformation of the T-loop requires correct handling and processing by repair enzymes. Uncontrolled uncapping is therefore a powerful cause of genomic instability, and loss of telomeres shortens replicative lifespan; both are hallmarks of WS.
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4.3. Are telomeres defective in WS?
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The major clinical characteristics of WS are premature ageing, presumably resulting from the highly premature replicative senescence, and elevated cancer risk, which is caused by excess genome instability. Since replicative senescence is caused, at least in part, by telomere shortening, and chromosome fusions result from telomere loss, it has been of major importance to determine whether telomeres are indeed defective in WS cells, and whether WRN plays any role in telomere maintenance. Human WS cells in culture show elevated rates of telomere loss [124]. Contradictory to this, however, are data from single telomere length analysis (STELA) that suggest WS cells do not experience exceptional rates of telomere shortening, at least in clonal populations, though in bulk cultures of WS fibroblast, telomere loss ranges from a normal 99bp/PD to a four fold increase at 355 bp/PD [125].
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Support for the importance of telomeric dysfunction in WS replicative senescence comes from studies of mouse models that are null for WRN. However, mice lacking WRN do not exhibit the premature ageing symptoms seen in humans [126] because laboratory mouse strains possess much longer telomeres than humans (40-80kb compared to 2-10kb) and detectable levels of telomerase even in somatic cells [127]. When mice deficient in telomerase are bred for several generations to reduce their telomere lengths to that approaching the normal human mean, removal of WRN gives similar premature ageing characteristics to those seen in human WS [128, 129]. Crucially, later-generation telomerase-null mice that still retain longer telomeres do not show this phenotype even though premature senescence is seen in their littermates that have short telomeres. Hence short telomeres combined with lack of WRN results in premature ageing.
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Figure 4.
Roles of WRN at the telomere include unwinding of G4 DNA, that would otherwise lead to replication fork stalling, and repair of oxidative damage to which the telomeric DNA is exquisitely sensitive.
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4.4. WRN helicase and exonuclease co-operate at the telomere
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The repetitive nature of telomeric DNA arises as a consequence of the short RNA template within telomerase; this, combined with the G-rich nature leads to these sequences forming secondary structures called G-quadruplexes, which stall replication machinery much as any bulky lesion or DNA gap or break will. It is therefore essential for cells to unwind telomeric DNA ahead of the replication fork to prevent stalling, or worse, collapse. As discussed above, D-loops, recombination intermediates and G-quadruplexes may all require WRN and other RecQ helicases to remove these blockages (Figure 4). Under experimental conditions in vitro, WRN localises to a sub-set of telomeres during S-phase without the induction of stress [29], and is enriched when cells are subjected to damaging agents that cause replication stress such as CPT. Thus WRN catalysis is needed to police both endogenous replication fork blocks and induced damage.
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WRN interacts with many of the proteins making up the shelterin complex or telosome [130-133] (see also Figure 3, above). Such interactions are likely to have functional consequences: for example, POT1 stimulates WRN helicase activity on linear and D-loop structures in vitro [134], whilst the presence of TRF1 and TRF2 can modulate their activity. TRF2 recruits WRN to D-loops and therefore stimulates unwinding [134], but it inhibits the helicase activity of WRN if binding to telomeric HJ substrates [135].
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There are fewer pathways for replication fork recovery at telomeric ends because of the lack of downstream origins [136]. This obviously increases the need for proteins such as WRN that can dissolve or resolve replication blocks and promote fork progression before irreversible fork collapse occurs. One such block is G-quadruplex DNA: it has been shown to stall the major replicative polymerase δ [72]. G-quadruplex structures can arise spontaneously in single-stranded telomeric sequence [137] and can be suppressed by the binding of POT1 to release single stranded telomeric sequence during uncapping [138]. WRN preferentially unwinds G-quadruplex DNA [139] and its presence will suppress polymerase δ stalling [72], suggesting it is a good candidate for this role.
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Interestingly, WRN – the only human RecQ helicase to also have exonuclease activity – unwinds D-loops in vitro in the absence of other proteins, using co-ordinate activity of both its helicase and exonuclease functions (RecQ helicase activity on these substrates is not particularly processive without stimulation for example by RPA [140]). The catalytic subunit of DNA-PK has also been shown to interact with WRN at telomeres [141], acting to suppress its exonuclease function and allow longer tracts to be unwound by the helicase activity. Therefore in the presence of DNA-PKcs, WRN processing of telomeric DNA does not shorten telomeric ends.
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4.5. WRN acts on the lagging strand during telomere replication
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Despite these detailed studies, the exact catalytic role(s) of WRN in telomere maintenance are still not fully defined. There is good evidence that cells lacking WRN have defective lagging strand synthesis at the telomere [142], as metaphase chromosomes in WRN helicase-deficient cells show a characteristic (if low-level) loss of telomeric sequence on one but not both sister chromatids. This is called sister telomere loss (STL), and suggests dysfunctional processing of one strand of the telomere during replication. The sister telomere lost is always the one resulting from lagging strand synthesis [142] This phenotype is thought to arise because in the absence of WRN activity, G-quadruplexes accumulate in the G-rich template strand and cause failure of lagging-telomere replication. Expression of active (but not inactive) telomerase suppresses STLs in cells lacking WRN [142], suggesting that sister telomere loss occurs during WRN-dependent processing of telomeres at times other than normal S phase when telomeres are uncapped for replication elongation.
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The low levels of STL that occur (if the experimental data from chromosomal FISH reflect the underlying levels) suggest that the events that cause the telomere loss might be difficult to process or close to irreparable, or are merely rare; they might be alternatively-processed in a pathway that does not induce loss. Conversely, the catalytic activity supplied by WRN might be substituted by other enzymes – its helicase role by one of the other RecQs, or its exonuclease function by another appropriate 3’-5’ exonuclease such as ExoI [143]. Whilst this has not yet been determined, however it is notable that cells deficient in BLM also show telomeric defects, although these are not the end-fusions arising from DSB repair as seen with WRN, but seem to be catenated associations possibly from aberrant HR [131]. BLM may thus have a role in resolving late-replicating DNA intermediates at telomeres distinct from WRN, as the rate of telomere dysfunction seen in cells with either single-null genotype is exacerbated in a double null [144].
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Since the processing of Okazaki fragments during lagging strand synthesis gives rise to regions of ssDNA, and G-rich sequences have a tendency to form G-quadruplex structures spontaneously, at the telomere there is increased likelihood of G-quadruplex formation in the single-stranded tracts. POT1 cannot actively dissociate the structure by binding, strongly suggesting that the G-quadruplex must first be dissociated before POT1 can bind and protect the telomeric sequence, and implicating a role for WRN in removing the replication block before problems arise (see review [145]). Interestingly, the available levels of POT1 may modulate the coupling of the leading and lagging strands at telomeres in the absence of WRN, allowing uncoupled synthesis of leading strand without processing of the lagging strand block [146].
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Supporting this hypothesis, recent research in yeast suggests an alternative protein that may function to suppress G-quadruplex formation at telomeres, but this time on the leading strand. Pif1 is a 5’-3’ helicase that negatively regulates telomere length [147]. Loss of Pif1 leads to slow replication fork progression, and in vitro Pif1 can unwind replication substrates [148]. Recently it was shown that cells without Pif1 have chromosome breakage at sites of G-tracts, and Pif1 can unwind G-quadruplex DNA that forms in the leading strand [149]. The higher eukaryote C. elegans also possesses a helicase (DOG-1) that is able to inhibit loss of guanine tracts, presumably by suppression of G-quadruplex structures [150]. It is tempting to speculate that genome surveillance utilises Pif1 on the leading strand and WRN on the lagging strand to suppress G-quadruplex formation and subsequent replication fork blockage at sites of high guanine content such as fragile sites and telomeric sequence.
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The loss of WRN in this putative mechanism inherently implies loss specifically of lagging-strand DNA at the telomeres. In this model, the rarity of STL may be explained by a low rate of G-quadruplex formation at single-stranded telomeric tracts during Okazaki fragment replication, the ability of BLM (or another RecQ) to substitute for WRN, or the specific need for WRN in a small subset of these events – perhaps because exonuclease processing is also required. The WRN exonuclease activity is itself specifically implicated in processing of the 3’-end of the telomere, although other nucleases such as ExoI or perhaps FEN-1 [151] might possess the capability to substitute for WRN. Addition of exogenous DNA oligonucleotides homologous to the 3’-overhang structure of an uncapped telomeric end to cells lacking WRN results in an increase in DNA damage responses and ultimately cell senescence [152].
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The loss of WRN in telomerase-positive cells in vivo causes the generation of extrachromosomal telomeric structures [153], [154] and this requires both helicase and exonuclease activities. WRN has exonuclease activity here that requires telomeric sequence in both double-stranded and single-stranded portions, and shows a characteristic limited degradation pattern [155]. TRF2 recruits WRN to telomeric sequence and in vitro it synergistically enhances the ability of WRN to degrade the G-rich 3’-overhangs of telomeric D-loops substrates [132, 156]. POT1 inhibits WRN exonuclease activity here [155]. TRF2 or WRN alone exhibit little or no stimulation on these substrates. Non-telomeric substrates show similarly little WRN-dependent degradation, presumably because TRF2 does not bind/recruit and stimulate WRN exonuclease, whilst TRF2 bound to telomeric sequence completely inhibits the activity of other nucleases such as ExoIII [132]. WRN helicase and exonuclease, together with TRF2, POT1, and Ku therefore probably act together to prevent telomeric free ends from becoming substrates for HR or other aberrant pathways. Taken together, these results support the specificity of WRN exonuclease in reducing the length of the telomeric 3’-end to the optimal length for regeneration of the T-loop after replication, and suppression of extrachromosomal telomeric circles.
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4.6. WRN may be important in ALT
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Telomeres can be lengthened without the use of telomerase using recombination to generate the template DNA needed. In yeast, this ALT[1] - pathway requires Sgs1 (the RecQ homologue in S. cerevisiae), for which WRN and BLM may both partially substitute [131, 157, 158]. Both WRN and BLM have also been seen to interact with telomeric DNA in human cells that utilize the ALT pathway [29, 130, 131], albeit only a small proportion. Although the ALT pathways are not yet elucidated, most models suggest recombinational mechanisms where strand invasion into telomeric DNA of the same (or different) chromosome or chromatid is utilized as template for resynthesis (e.g. see [159, 160]). BLM-deficient cells show elevated rates of sister chromatid exchange [161] that were not detected in cells lacking WRN, however finer resolution experiments suggest that WS cells do show elevated SCE, but only at telomeres [162, 163]. The WS mouse models with shortened telomeres (described in section 4.3 above) show elevated levels of this telomere-specific SCE [164], as do cells deficient in POT1, or Ku and TRF2 together [165]. Ku stimulates both helicase and exonuclease activities of WRN [166, 167], and suppresses telomeric recombination brought on by the absence of TRF2 and consequent telomeric uncapping [110]. Taken together, these data suggest that WRN is prominent in a pathway that specifically suppresses telomeric recombination or dissolves junctions, and it is at least partially distinct from the role of BLM.
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4.7. Telomeric DNA is hypersensitive to oxidative lesions – a further role for WRN
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The G-rich nature of telomeric sequence means it is a rich target for oxidative damage[1] - [168], and oxidative stress and mitochondrial dysfunction often give rise to concomitant telomeric dysfunction [169], which can be reduced using antioxidants. Notably, artificial replicative senescence can be induced with a burst of oxidative damage [170, 171]. Oxidation of telomeric bases can disrupt DNA binding of TRF1 and TRF2, and presumably therefore telosome and T-loop assembly [166], whilst over-expression of TRF2 protect cells with shortened telomeres from early senescence [172].
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WRN is a central component of base excision repair (BER) of oxidative lesions, interacting with most of the key proteins in the pathway such as pol beta (β) and FEN1 [173, 174]. Consistent with an important role for WRN in removing oxidative lesions, WS cells show increased oxidative damage [175, 176].
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It has been shown that D-loops containing oxidised bases can be bound by POT1 and are a preferred substrate for WRN [177]. The strand-displacement activity of pol β, the repair polymerase in BER, is also stimulated by TRF2 [178], and TRF1, TRF2 and POT1 can enhance all the constituent steps of long patch BER [179]. As previously mentioned, WRN itself can also stimulate TLS pols to replicate past an oxidative block [84]. This suggests active recruitment and stimulation of anti-oxidative damage processes at telomeres involving RecQ helicases. These findings partly illustrate how the activities of RecQ helicases are tightly controlled by the surrounding milieu in order to differentiate their roles in replication and repair.
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Although the wider significance of all these data is yet to be determined, it is obvious that WRN is active at multiple points in telomere replication and repair.
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5. Conclusions
\n\t\t\t
The helicase/exonuclease WRN has been shown to be critically important in DNA replication, acting to enhance fidelity, regulate template unwinding to prevent fork stalling at unusual structures, assist with replication fork restart and/or enhance processivity post-restart, aid translesion synthesis over otherwise unreplicatable lesions, promote regression of stalled replication forks to allow error-free restart, modulate recombination at collapsed replication forks, and aid telomere replication. It is recruited to sites of DNA synthesis, possibly through association with the sliding clamp PCNA, and to sites of stalled/collapsed forks probably by RPA in concert with the S phase checkpoint kinase ATR and its downstream effectors and mediators Chk1, Rad53, Mec1 and Mrc1. Loss of WRN results in high levels of chromosomal instability and elevated cancer risk, and the defects in DNA replication on WRN loss also results in premature onset of replicative senescence with concomitant organismal ageing, manifest as progeroid Werner’s syndrome. While much has been discovered as to WRN’s mode of action, there is still an enormous amount to learn as to how its activities are co-ordinated with the cell during DNA replication.
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Acknowledgments
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We thank Hayley Lees (Department of Biochemistry, University of Oxford) for critical reading of the manuscript. We gratefully acknowledge support from the Economic and Social Sciences Research Council of Great Britain (ESRC) grant [ES/G037086/1] under the cross-council New Dynamics of Ageing initiative.
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/39662.pdf",chapterXML:"https://mts.intechopen.com/source/xml/39662.xml",downloadPdfUrl:"/chapter/pdf-download/39662",previewPdfUrl:"/chapter/pdf-preview/39662",totalDownloads:1790,totalViews:932,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"March 7th 2012",dateReviewed:"July 11th 2012",datePrePublished:null,datePublished:"February 20th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/39662",risUrl:"/chapter/ris/39662",book:{slug:"the-mechanisms-of-dna-replication"},signatures:"Lynne S. Cox and Penelope A. Mason",authors:[{id:"152703",title:"Dr.",name:"Lynne",middleName:null,surname:"Cox",fullName:"Lynne Cox",slug:"lynne-cox",email:"lynne.cox@bioch.ox.ac.uk",position:null,institution:null},{id:"153944",title:"Dr.",name:"Penelope",middleName:null,surname:"Mason",fullName:"Penelope Mason",slug:"penelope-mason",email:"penelope.mason@bioch.ox.ac.uk",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. WRN is a RecQ helicase/exonuclease required for genome stability and to prevent premature ageing",level:"2"},{id:"sec_1_3",title:"1.1.1. Clinical phenotype of Werner’s syndrome",level:"3"},{id:"sec_3_2",title:"1.2. Cellular phenotype on WRN loss",level:"2"},{id:"sec_4_2",title:"1.3. WRN protein",level:"2"},{id:"sec_5_2",title:"1.4. WRN orthologues",level:"2"},{id:"sec_6_2",title:"1.5. S phase defects in WS cells",level:"2"},{id:"sec_8",title:"2. WRN at the replication fork",level:"1"},{id:"sec_8_2",title:"2.1. Okazaki fragment processing",level:"2"},{id:"sec_9_2",title:"2.2. Proof-reading during processive DNA synthesis",level:"2"},{id:"sec_11",title:"3. Replication fork stalling – the role of WRN",level:"1"},{id:"sec_11_2",title:"3.1. High rates of replication fork stalling in WS",level:"2"},{id:"sec_12_2",title:"3.2. Causes of fork stalling",level:"2"},{id:"sec_13_2",title:"3.3. Dealing with unusual structures before they arrest the fork",level:"2"},{id:"sec_14_2",title:"3.4. Is WRN involved in fork restart or progression following restart? ",level:"2"},{id:"sec_15_2",title:"3.5. Error-prone translesional synthesis to relieve the replication block",level:"2"},{id:"sec_16_2",title:"3.6. WRN suppresses illegitimate recombination at stalled forks",level:"2"},{id:"sec_17_2",title:"3.7. Template switching at stalled forks",level:"2"},{id:"sec_18_2",title:"3.8. How is WRN recruited to stalled forks?",level:"2"},{id:"sec_19_2",title:"3.9. Role of WRN at stalled forks on the lagging strand",level:"2"},{id:"sec_21",title:"4. Involvement of WRN in telomere maintenance ",level:"1"},{id:"sec_21_2",title:"4.1. Telomere structure and replication",level:"2"},{id:"sec_22_2",title:"4.2. Telomere shortening leads to replicative senescence and genome instability",level:"2"},{id:"sec_23_2",title:"4.3. Are telomeres defective in WS?",level:"2"},{id:"sec_24_2",title:"4.4. WRN helicase and exonuclease co-operate at the telomere ",level:"2"},{id:"sec_25_2",title:"4.5. WRN acts on the lagging strand during telomere replication",level:"2"},{id:"sec_26_2",title:"4.6. WRN may be important in ALT",level:"2"},{id:"sec_27_2",title:"4.7. Telomeric DNA is hypersensitive to oxidative lesions – a further role for WRN ",level:"2"},{id:"sec_29",title:"5. Conclusions",level:"1"},{id:"sec_30",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLarizza\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoversi\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVolpi\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\tRothmund-Thomson syndrome\n\t\t\t\t\tOrphanet J Rare Dis\n\t\t\t\t\tvol. 5, 2\n\t\t\t\t\n\t\t\t'},{id:"B2",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoto\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tClinical characteristics of Werner syndrome and other premature aging syndromes: pattern of aging in progeroid syndromes From premature gray hair to helicase- Werner syndrome: implications for aging and cancer, M. Goto and R. W. 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M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHisama\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlisch\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatthews\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakura\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOuais\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartin\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMulligan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchellenberg\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996\n\t\t\t\t\tPositional cloning of the Werner’s syndrome gene,\n\t\t\t\t\tScience\n\t\t\t\t\t272\n\t\t\t\t\t5259\n\t\t\t\t\t258\n\t\t\t\t\t262\n\t\t\t\t\n\t\t\t'},{id:"B15",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon Kobbe\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV.A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tA nucleolar targeting sequence in the Werner syndrome protein resides within residues 949-1092\n\t\t\t\t\tJ Cell Sci\n\t\t\t\t\t115\n\t\t\t\t\t3901\n\t\t\t\t\t3907\n\t\t\t\t\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarciniak\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLombard\n\t\t\t\t\t\t\tD. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tF. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuarente\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tNucleolar localization of the Werner syndrome protein in human cells\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t95\n\t\t\t\t\t12\n\t\t\t\t\t6887\n\t\t\t\t\t6892\n\t\t\t\t\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRodriguez-Lopez\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIborra\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tAsymmetry of DNA replication fork progression in Werner’s syndrome\n\t\t\t\t\tAging Cell\n\t\t\t\t\t1\n\t\t\t\t\t1\n\t\t\t\t\t30\n\t\t\t\t\t39\n\t\t\t\t\n\t\t\t'},{id:"B18",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRodriguez-Lopez\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNehlin\n\t\t\t\t\t\t\tJ. O.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIborra\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWarren\n\t\t\t\t\t\t\tA. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tCharacterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner’s syndrome, and an essential replication factor, PCNA\n\t\t\t\t\tMech Ageing Dev\n\t\t\t\t\t124\n\t\t\t\t\t2\n\t\t\t\t\t167\n\t\t\t\t\t174\n\t\t\t\t\n\t\t\t'},{id:"B19",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConstantinou\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTarsounas\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarow\n\t\t\t\t\t\t\tJ. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWest\n\t\t\t\t\t\t\tS. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tWerner’s syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest\n\t\t\t\t\tEMBO Rep\n\t\t\t\t\t1\n\t\t\t\t\t1\n\t\t\t\t\t80\n\t\t\t\t\t84\n\t\t\t\t\n\t\t\t'},{id:"B20",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGray\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOshima\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMian\n\t\t\t\t\t\t\tI. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCampisi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tThe premature ageing syndrome protein, WRN, is a 3’-->5’ exonuclease\n\t\t\t\t\tNat Genet\n\t\t\t\t\t20\n\t\t\t\t\t2\n\t\t\t\t\t114\n\t\t\t\t\t116\n\t\t\t\t\n\t\t\t'},{id:"B21",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeresten\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOshima\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEllis\n\t\t\t\t\t\t\tN. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCampisi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tCharacterization of the human and mouse WRN 3’-->5’ exonuclease\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t28\n\t\t\t\t\t12\n\t\t\t\t\t2396\n\t\t\t\t\t2405\n\t\t\t\t\n\t\t\t'},{id:"B22",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarrigan\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMomand\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPerrino\n\t\t\t\t\t\t\tF. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tWRN exonuclease activity is blocked by DNA termini harboring 3’ obstructive groups\n\t\t\t\t\tMech Ageing Dev\n\t\t\t\t\t128\n\t\t\t\t\t3\n\t\t\t\t\t259\n\t\t\t\t\t266\n\t\t\t\t\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOzgenc\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tCurrent advances in unraveling the function of the Werner syndrome protein\n\t\t\t\t\tMutat Res\n\t\t\t\t\t577\n\t\t\t\t\t1-2\n\t\t\t\t\t237\n\t\t\t\t\t251\n\t\t\t\t\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXue\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRatcliff\n\t\t\t\t\t\t\tG. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavis-Searles\n\t\t\t\t\t\t\tP. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGray\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tErie\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRedinbo\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tA minimal exonuclease domain of WRN forms a hexamer on DNA and possesses both 3’- 5’ exonuclease and 5’-protruding strand endonuclease activities\n\t\t\t\t\tBiochemistry\n\t\t\t\t\t41\n\t\t\t\t\t9\n\t\t\t\t\t2901\n\t\t\t\t\t2912\n\t\t\t\t\n\t\t\t'},{id:"B25",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tLength-dependent degradation of single-stranded 3’ ends by the Werner syndrome protein (WRN): implications for spatial orientation and coordinated 3’ to 5’ movement of its ATPase/helicase and exonuclease domains\n\t\t\t\t\tBMC Mol Biol\n\t\t\t\t\t7\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B26",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGray\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamath-Loeb\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlank\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSopher\n\t\t\t\t\t\t\tB. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartin\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOshima\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997\n\t\t\t\t\tThe Werner syndrome protein is a DNA helicase\n\t\t\t\t\tNat Genet\n\t\t\t\t\t17\n\t\t\t\t\t1\n\t\t\t\t\t100\n\t\t\t\t\t103\n\t\t\t\t\n\t\t\t'},{id:"B27",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWaheed\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSommers\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tBiochemical characterization of the DNA substrate specificity of Werner syndrome helicase\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t277\n\t\t\t\t\t26\n\t\t\t\t\t23236\n\t\t\t\t\t23245\n\t\t\t\t\n\t\t\t'},{id:"B28",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tUnwinding the molecular basis of the Werner syndrome\n\t\t\t\t\tMech Ageing Dev\n\t\t\t\t\t122\n\t\t\t\t\t9\n\t\t\t\t\t921\n\t\t\t\t\t944\n\t\t\t\t\n\t\t\t'},{id:"B29",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOtterlei\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGraakjaer\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBruheim\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDawut\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKolvraa\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMay\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeidman\n\t\t\t\t\t\t\tM. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tThe Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2\n\t\t\t\t\tMol Cell\n\t\t\t\t\t14\n\t\t\t\t\t6\n\t\t\t\t\t763\n\t\t\t\t\t774\n\t\t\t\t\n\t\t\t'},{id:"B30",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitano\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHakoshima\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tStructural basis for DNA strand separation by the unconventional winged-helix domain of RecQ helicase WRN\n\t\t\t\t\tStructure\n\t\t\t\t\t18\n\t\t\t\t\t2\n\t\t\t\t\t177\n\t\t\t\t\t187\n\t\t\t\t\n\t\t\t'},{id:"B31",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitano\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshihara\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHakoshima\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tCrystal structure of the HRDC domain of human Werner syndrome protein, WRN\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t282\n\t\t\t\t\t4\n\t\t\t\t\t2717\n\t\t\t\t\t2728\n\t\t\t\t\n\t\t\t'},{id:"B32",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHartung\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuchta\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tThe RecQ gene family in plants\n\t\t\t\t\tJ Plant Physiol\n\t\t\t\t\t163\n\t\t\t\t\t3\n\t\t\t\t\t287\n\t\t\t\t\t296\n\t\t\t\t\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheng\n\t\t\t\t\t\t\tW. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tJunction of RecQ helicase biochemistry and human disease\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t279\n\t\t\t\t\t18\n\t\t\t\t\t18099\n\t\t\t\t\t18102\n\t\t\t\t\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClancy\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoubriak\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaunders\n\t\t\t\t\t\t\tR. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tModeling Werner Syndrome in Drosophila melanogaster: hyper-recombination in flies lacking WRN-like exonuclease\n\t\t\t\t\tAnn N Y Acad Sci\n\t\t\t\t\t1119\n\t\t\t\t\t274\n\t\t\t\t\t288\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoubriak\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMason\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClancy\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDockray\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaunders\n\t\t\t\t\t\t\tR. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tDmWRNexo is a 3’-5’ exonuclease: phenotypic and biochemical characterization of mutants of the Drosophila orthologue of human WRN exonuclease\n\t\t\t\t\tBiogerontology\n\t\t\t\t\t10\n\t\t\t\t\t3\n\t\t\t\t\t267\n\t\t\t\t\t277\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMason\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoubriak\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobbins\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLasala\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaunders\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tThe Drosophila orthologue of progeroid human WRN exonuclease, DmWRNexo, cleaves replication substrates but is inhibited by uracil or abasic sites : Analysis of DmWRNexo activity in vitro\n\t\t\t\t\tAge (Dordr)\n\t\t\t\t\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaunders\n\t\t\t\t\t\t\tR. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoubriak\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClancy\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tIdentification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity\n\t\t\t\t\tAging Cell\n\t\t\t\t\t7\n\t\t\t\t\t3\n\t\t\t\t\t418\n\t\t\t\t\t425\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKetting\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHaverkamp\n\t\t\t\t\t\t\tT. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan Luenen\n\t\t\t\t\t\t\tH. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPlasterk\n\t\t\t\t\t\t\tR. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tMut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RNaseD\n\t\t\t\t\tCell\n\t\t\t\t\t99\n\t\t\t\t\t2\n\t\t\t\t\t133\n\t\t\t\t\t141\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYook\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHan\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoo\n\t\t\t\t\t\t\tH. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tA Werner syndrome protein homolog affects C. elegans development, growth rate, life span and sensitivity to DNA damage by acting at a DNA damage checkpoint\n\t\t\t\t\tDevelopment\n\t\t\t\t\t131\n\t\t\t\t\t11\n\t\t\t\t\t2565\n\t\t\t\t\t2575\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGartner\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHyun\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAhn\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoo\n\t\t\t\t\t\t\tH. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tThe Caenorhabditis elegans Werner syndrome protein functions upstream of ATR and ATM in response to DNA replication inhibition and double-strand DNA breaks\n\t\t\t\t\tPLoS Genet\n\t\t\t\t\t6\n\t\t\t\t\t1\n\t\t\t\t\te1000801\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHartung\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPlchova\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuchta\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tMolecular characterisation of RecQ homologues in Arabidopsis thaliana\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t28\n\t\t\t\t\t21\n\t\t\t\t\t4275\n\t\t\t\t\t4282\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDoe\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAhn\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDixon\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWhitby\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tMus81-Eme1 and Rqh1 involvement in processing stalled and collapsed replication forks\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t277\n\t\t\t\t\t36\n\t\t\t\t\t32753\n\t\t\t\t\t32759\n\t\t\t\t\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoot\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoehn\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRunger\n\t\t\t\t\t\t\tT. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartin\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992\n\t\t\t\t\tImpaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines\n\t\t\t\t\tExp Cell Res\n\t\t\t\t\t202\n\t\t\t\t\t2\n\t\t\t\t\t267\n\t\t\t\t\t273\n\t\t\t\t\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSidorova\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFolch\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMonnat\n\t\t\t\t\t\t\tR. 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A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarmakar\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPiotrowski\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDianova\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDianov\n\t\t\t\t\t\t\tG. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tWerner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity\n\t\t\t\t\tEMBO J\n\t\t\t\t\t20\n\t\t\t\t\t20\n\t\t\t\t\t5791\n\t\t\t\t\t5801\n\t\t\t\t\n\t\t\t'},{id:"B64",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSommers\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGary\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFriedrich-Heineken\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHubscher\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tThe interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t33\n\t\t\t\t\t21\n\t\t\t\t\t6769\n\t\t\t\t\t6781\n\t\t\t\t\n\t\t\t'},{id:"B65",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNick\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Elhinny\n\t\t\t\t\t\t\tZ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPursell\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKunkel\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tMechanisms for high fidelity DNA replication\n\t\t\t\t\t\n\t\t\t\t\t\tMolecular Themes in DNA Replication, L. S. 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A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012The Werner syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase delta\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t287\n\t\t\t\t\t15\n\t\t\t\t\t12480\n\t\t\t\t\t12490\n\t\t\t\t\n\t\t\t'},{id:"B69",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakeuchi\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanaoka\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoto\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkaoka\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHori\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyamoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1982\n\t\t\t\t\tAltered frequency of initiation sites of DNA replication in Werner’s syndrome cells\n\t\t\t\t\tHum Genet\n\t\t\t\t\t60\n\t\t\t\t\t4\n\t\t\t\t\t365\n\t\t\t\t\t368\n\t\t\t\t\n\t\t\t'},{id:"B70",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanaoka\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakeuchi\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoto\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyamoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHori\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985\n\t\t\t\t\tAutoradiographic studies of DNA replication in Werner’s syndrome cells\n\t\t\t\t\tAdv Exp Med Biol\n\t\t\t\t\t190\n\t\t\t\t\t439\n\t\t\t\t\t457\n\t\t\t\t\n\t\t\t'},{id:"B71",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFoiani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerrari\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiberi\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLopes\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLucca\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarini\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPellicioli\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuzi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFalconi\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPlevani\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tS-phase DNA damage checkpoint in budding yeast\n\t\t\t\t\tBiol Chem\n\t\t\t\t\t379\n\t\t\t\t\t8-9\n\t\t\t\t\t1019\n\t\t\t\t\t1023\n\t\t\t\t\n\t\t\t'},{id:"B72",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamath-Loeb\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohansson\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurgers\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFry\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tInteractions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t276\n\t\t\t\t\t19\n\t\t\t\t\t16439\n\t\t\t\t\t16446\n\t\t\t\t\n\t\t\t'},{id:"B73",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmmazzalorso\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPirzio\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBignami\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranchitto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPichierri\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery\n\t\t\t\t\tEMBO J\n\t\t\t\t\t29\n\t\t\t\t\t18\n\t\t\t\t\t3156\n\t\t\t\t\t3169\n\t\t\t\t\n\t\t\t'},{id:"B74",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurfuni\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Santis\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFederico\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBignami\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPichierri\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranchitto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tPerturbed replication induced genome-wide or at common fragile sites is differently managed in the absence of WRN\n\t\t\t\t\tCarcinogenesis\n\t\t\t\t\t33\n\t\t\t\t\t9\n\t\t\t\t\t1655\n\t\t\t\t\t63\n\t\t\t\t\n\t\t\t'},{id:"B75",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShah\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeng\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tM. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEckert\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tDNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D,\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t38\n\t\t\t\t\t4\n\t\t\t\t\t1149\n\t\t\t\t\t1162\n\t\t\t\t\n\t\t\t'},{id:"B76",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWashington\n\t\t\t\t\t\t\tM. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHaracska\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrakash\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrakash\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tEukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions\n\t\t\t\t\tNature\n\t\t\t\t\t406\n\t\t\t\t\t6799\n\t\t\t\t\t1015\n\t\t\t\t\t1019\n\t\t\t\t\n\t\t\t'},{id:"B77",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChoi\n\t\t\t\t\t\t\tJ.Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuengerich\n\t\t\t\t\t\t\tF.P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tKinetic evidence for inefficient and error-prone bypass across bulky N2-guanine DNA adducts by human DNA polymerase iota\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t281\n\t\t\t\t\t18\n\t\t\t\t\t12315\n\t\t\t\t\t12324\n\t\t\t\t\n\t\t\t'},{id:"B78",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNimonkar\n\t\t\t\t\t\t\tA. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOzsoy\n\t\t\t\t\t\t\tA. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGenschel\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tModrich\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKowalczykowski\n\t\t\t\t\t\t\tS. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tHuman exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t105\n\t\t\t\t\t44\n\t\t\t\t\t16906\n\t\t\t\t\t16911\n\t\t\t\t\n\t\t\t'},{id:"B79",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAggarwal\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSommers\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorris\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tDelineation of WRN helicase function with EXO1 in the replicational stress response\n\t\t\t\t\tDNA Repair (Amst)\n\t\t\t\t\t9\n\t\t\t\t\t7\n\t\t\t\t\t765\n\t\t\t\t\t776\n\t\t\t\t\n\t\t\t'},{id:"B80",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAggarwal\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tGenetic mutants illuminate the roles of RecQ helicases in recombinational repair or response to replicational stress\n\t\t\t\t\tCell Cycle\n\t\t\t\t\t9\n\t\t\t\t\t16\n\t\t\t\t\t3139\n\t\t\t\t\t3141\n\t\t\t\t\n\t\t\t'},{id:"B81",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsuda\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBebenek\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMasutani\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRogozin\n\t\t\t\t\t\t\tI. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanaoka\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKunkel\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tError rate and specificity of human and murine DNA polymerase eta\n\t\t\t\t\tJ Mol Biol\n\t\t\t\t\t312\n\t\t\t\t\t2\n\t\t\t\t\t335\n\t\t\t\t\t346\n\t\t\t\t\n\t\t\t'},{id:"B82",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuan\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXin\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRajpal\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tHuman DNA polymerase kappa synthesizes DNA with extraordinarily low fidelity\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t28\n\t\t\t\t\t21\n\t\t\t\t\t4147\n\t\t\t\t\t4156\n\t\t\t\t\n\t\t\t'},{id:"B83",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVasquez Del\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarpio\n\t\t\t\t\t\t\tT. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilverstein\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLone\n\t\t\t\t\t\t\tM. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSwan\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChoudhury\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrakash\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAggarwal\n\t\t\t\t\t\t\tA. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tStructure of human DNA polymerase kappa inserting dATP opposite an 8-OxoG DNA lesion\n\t\t\t\t\tPLoS One\n\t\t\t\t\t4\n\t\t\t\t\t6\n\t\t\t\t\te5766\n\t\t\t\t\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamath-Loeb\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLan\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakajima\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYasui\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tWerner syndrome protein interacts functionally with translesion DNA polymerases\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t104\n\t\t\t\t\t25\n\t\t\t\t\t10394\n\t\t\t\t\t10399\n\t\t\t\t\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLozada\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWold\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tMolecular cooperation between the Werner syndrome protein and replication protein A in relation to replication fork blockage\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t286\n\t\t\t\t\t5\n\t\t\t\t\t3497\n\t\t\t\t\t3508\n\t\t\t\t\n\t\t\t'},{id:"B86",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSommers\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDriscoll\n\t\t\t\t\t\t\tH. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUzdilla\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tT. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tThe exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t278\n\t\t\t\t\t26\n\t\t\t\t\t23487\n\t\t\t\t\t23496\n\t\t\t\t\n\t\t\t'},{id:"B87",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranchitto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPirzio\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tProsperi\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSapora\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBignami\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPichierri\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tReplication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway\n\t\t\t\t\tJ Cell Biol\n\t\t\t\t\t183\n\t\t\t\t\t2\n\t\t\t\t\t241\n\t\t\t\t\t252\n\t\t\t\t\n\t\t\t'},{id:"B88",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tByun\n\t\t\t\t\t\t\tT. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPacek\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYee\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalter\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCimprich\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tFunctional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t19\n\t\t\t\t\t9\n\t\t\t\t\t1040\n\t\t\t\t\t1052\n\t\t\t\t\n\t\t\t'},{id:"B89",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSingleton\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScaife\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRaven\n\t\t\t\t\t\t\tN. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWigley\n\t\t\t\t\t\t\tD. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tCrystallization and preliminary X-ray analysis of RecG, a replication-fork reversal helicase from Thermotoga maritima complexed with a three-way DNA junction\n\t\t\t\t\tActa Crystallogr D Biol Crystallogr\n\t\t\t\t\t57\n\t\t\t\t\t11\n\t\t\t\t\t1695\n\t\t\t\t\t1696\n\t\t\t\t\n\t\t\t'},{id:"B90",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSingleton\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScaife\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWigley\n\t\t\t\t\t\t\tD. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tStructural analysis of DNA replication fork reversal by RecG\n\t\t\t\t\tCell\n\t\t\t\t\t107\n\t\t\t\t\t1\n\t\t\t\t\t79\n\t\t\t\t\t89\n\t\t\t\t\n\t\t\t'},{id:"B91",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCourcelle\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDonaldson\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChow\n\t\t\t\t\t\t\tK. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCourcelle\n\t\t\t\t\t\t\tC. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tDNA damage-induced replication fork regression and processing in Escherichia coli\n\t\t\t\t\tScience\n\t\t\t\t\t299\n\t\t\t\t\t5609\n\t\t\t\t\t1064\n\t\t\t\t\t1067\n\t\t\t\t\n\t\t\t'},{id:"B92",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOtterlei\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSommers\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDriscoll\n\t\t\t\t\t\t\tH. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDianov\n\t\t\t\t\t\t\tG. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKao\n\t\t\t\t\t\t\tH. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBambara\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tWRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork\n\t\t\t\t\tMol Biol Cell\n\t\t\t\t\t15\n\t\t\t\t\t2\n\t\t\t\t\t734\n\t\t\t\t\t750\n\t\t\t\t\n\t\t\t'},{id:"B93",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOtterlei\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBruheim\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAhn\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBussen\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarmakar\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaynton\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tWerner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest\n\t\t\t\t\tJ Cell Sci\n\t\t\t\t\t119\n\t\t\t\t\t5137\n\t\t\t\t\t5146\n\t\t\t\t\n\t\t\t'},{id:"B94",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarale\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tThe Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) holliday junctions to functional replication forks\n\t\t\t\t\tBiochemistry\n\t\t\t\t\t50\n\t\t\t\t\t32\n\t\t\t\t\t6774\n\t\t\t\t\t6788\n\t\t\t\t\n\t\t\t'},{id:"B95",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPichierri\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosselli\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tThe DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways\n\t\t\t\t\tEMBO J\n\t\t\t\t\t23\n\t\t\t\t\t5\n\t\t\t\t\t1178\n\t\t\t\t\t1187\n\t\t\t\t\n\t\t\t'},{id:"B96",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBennetzen\n\t\t\t\t\t\t\tM. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarino\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPultz\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorselli\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFaergeman\n\t\t\t\t\t\t\tN. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKroemer\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAndersen\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tPhosphoproteomic analysis of cells treated with longevity-related autophagy inducers\n\t\t\t\t\tCell Cycle\n\t\t\t\t\t11\n\t\t\t\t\t9\n\t\t\t\t\t1827\n\t\t\t\t\t1840\n\t\t\t\t\n\t\t\t'},{id:"B97",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPatro\n\t\t\t\t\t\t\tB. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrohlich\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStevnsner\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tWRN helicase regulates the ATR-CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I-DNA covalent complexes\n\t\t\t\t\tJ Cell Sci\n\t\t\t\t\t124\n\t\t\t\t\t3967\n\t\t\t\t\t3979\n\t\t\t\t\n\t\t\t'},{id:"B98",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPichierri\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNicolai\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCignolo\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBignami\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranchitto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tThe RAD9-RAD1-HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling\n\t\t\t\t\tOncogene\n\t\t\t\t\t31\n\t\t\t\t\t23\n\t\t\t\t\t2809\n\t\t\t\t\t2823\n\t\t\t\t\n\t\t\t'},{id:"B99",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSvoboda\n\t\t\t\t\t\t\tD.L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVos\n\t\t\t\t\t\t\tJ.M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1995\n\t\t\t\t\tDifferential replication of a single, UV-induced lesion in the leading or lagging strand by a human cell extract: fork uncoupling or gap formation\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t92\n\t\t\t\t\t26\n\t\t\t\t\t11975\n\t\t\t\t\t11979\n\t\t\t\t\n\t\t\t'},{id:"B100",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Inerney\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Donnell\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tFunctional uncoupling of twin polymerases: mechanism of polymerase dissociation from a lagging-strand block\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t279\n\t\t\t\t\t20\n\t\t\t\t\t21543\n\t\t\t\t\t21551\n\t\t\t\t\n\t\t\t'},{id:"B101",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeller\n\t\t\t\t\t\t\tR.C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarians\n\t\t\t\t\t\t\tK.J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tReplisome assembly and the direct restart of stalled replication forks\n\t\t\t\t\tNat Rev Mol Cell Biol\n\t\t\t\t\t7\n\t\t\t\t\t12\n\t\t\t\t\t932\n\t\t\t\t\t943\n\t\t\t\t\n\t\t\t'},{id:"B102",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tThe Bloom’s syndrome helicase suppresses crossing over during homologous recombination\n\t\t\t\t\tNature\n\t\t\t\t\t426\n\t\t\t\t\t6968\n\t\t\t\t\t870\n\t\t\t\t\t874\n\t\t\t\t\n\t\t\t'},{id:"B103",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChan\n\t\t\t\t\t\t\tK. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRalf\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBernstein\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarcia\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVindigni\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJanscak\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKeck\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tThe HRDC domain of BLM is required for the dissolution of double Holliday junctions\n\t\t\t\t\tEMBO J\n\t\t\t\t\t24\n\t\t\t\t\t14\n\t\t\t\t\t2679\n\t\t\t\t\t2687\n\t\t\t\t\n\t\t\t'},{id:"B104",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSowd\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tThe Werner syndrome helicase/exonuclease processes mobile D-loops through branch migration and degradation\n\t\t\t\t\tPLoS One\n\t\t\t\t\t4\n\t\t\t\t\t3\n\t\t\t\t\te4825\n\t\t\t\t\n\t\t\t'},{id:"B105",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamath-Loeb\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohansson\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurgers\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tFunctional interaction between the Werner Syndrome protein and DNA polymerase delta\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t97\n\t\t\t\t\t9\n\t\t\t\t\t4603\n\t\t\t\t\t4608\n\t\t\t\t\n\t\t\t'},{id:"B106",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKunkel\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSabatino\n\t\t\t\t\t\t\tR. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBambara\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1987\n\t\t\t\t\tExonucleolytic proofreading by calf thymus DNA polymerase delta\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t84\n\t\t\t\t\t14\n\t\t\t\t\t4865\n\t\t\t\t\t4869\n\t\t\t\t\n\t\t\t'},{id:"B107",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamath-Loeb\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoeb\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFry\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tThe Werner syndrome protein is distinguished from the Bloom syndrome protein by its capacity to tightly bind diverse DNA structures\n\t\t\t\t\tPLoS One\n\t\t\t\t\t7\n\t\t\t\t\t1\n\t\t\t\t\te30189\n\t\t\t\t\n\t\t\t'},{id:"B108",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBukowy\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarrigan\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamsden\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTudek\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStevnsner\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tWRN Exonuclease activity is blocked by specific oxidatively induced base lesions positioned in either DNA strand\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t36\n\t\t\t\t\t15\n\t\t\t\t\t4975\n\t\t\t\t\t4987\n\t\t\t\t\n\t\t\t'},{id:"B109",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaser\n\t\t\t\t\t\t\tR.S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDePinho\n\t\t\t\t\t\t\tR.A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tTelomeres and the DNA damage response: why the fox is guarding the henhouse,\n\t\t\t\t\tDNA Repair (Amst)\n\t\t\t\t\t3\n\t\t\t\t\t8-9\n\t\t\t\t\t979\n\t\t\t\t\t988\n\t\t\t\t\n\t\t\t'},{id:"B110",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\td’Adda\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tdi Fagagna\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tS. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tFunctional links between telomeres and proteins of the DNA-damage response\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t18\n\t\t\t\t\t15\n\t\t\t\t\t1781\n\t\t\t\t\t1799\n\t\t\t\t\n\t\t\t'},{id:"B111",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGriffith\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tComeau\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosenfield\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStansel\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBianchi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoss\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Lange\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tMammalian telomeres end in a large duplex loop\n\t\t\t\t\tCell\n\t\t\t\t\t97\n\t\t\t\t\t4\n\t\t\t\t\t503\n\t\t\t\t\t514\n\t\t\t\t\n\t\t\t'},{id:"B112",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Lange\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tShelterin: the protein complex that shapes and safeguards human telomeres\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t19\n\t\t\t\t\t18\n\t\t\t\t\t2100\n\t\t\t\t\t2110\n\t\t\t\t\n\t\t\t'},{id:"B113",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBroccoli\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmogorzewska\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChong\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Lange\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997\n\t\t\t\t\tHuman telomeres contain two distinct Myb-related proteins, TRF1 and TRF2\n\t\t\t\t\tNat Genet\n\t\t\t\t\t17\n\t\t\t\t\t2\n\t\t\t\t\t231\n\t\t\t\t\t235\n\t\t\t\t\n\t\t\t'},{id:"B114",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Connor\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSongyang\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tTelosome, a mammalian telomere-associated complex formed by multiple telomeric proteins\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t279\n\t\t\t\t\t49\n\t\t\t\t\t51338\n\t\t\t\t\t51342\n\t\t\t\t\n\t\t\t'},{id:"B115",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaumann\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCech\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tPot1, the putative telomere end-binding protein in fission yeast and humans\n\t\t\t\t\tScience\n\t\t\t\t\t292\n\t\t\t\t\t5519\n\t\t\t\t\t1171\n\t\t\t\t\t1175\n\t\t\t\t\n\t\t\t'},{id:"B116",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Donovan\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomiyama\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuterman\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdler\n\t\t\t\t\t\t\tN. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKemeny\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWolkowitz\n\t\t\t\t\t\t\tO. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlackburn\n\t\t\t\t\t\t\tE. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEpel\n\t\t\t\t\t\t\tE. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tStress appraisals and cellular aging: a key role for anticipatory threat in the relationship between psychological stress and telomere length\n\t\t\t\t\tBrain Behav Immun\n\t\t\t\t\t26\n\t\t\t\t\t4\n\t\t\t\t\t573\n\t\t\t\t\t579\n\t\t\t\t\n\t\t\t'},{id:"B117",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEpel\n\t\t\t\t\t\t\tE. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDhabhar\n\t\t\t\t\t\t\tF. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWolkowitz\n\t\t\t\t\t\t\tO. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuterman\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaran\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlackburn\n\t\t\t\t\t\t\tE. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tDynamics of telomerase activity in response to acute psychological stress\n\t\t\t\t\tBrain Behav Immun\n\t\t\t\t\t24\n\t\t\t\t\t4\n\t\t\t\t\t531\n\t\t\t\t\t539\n\t\t\t\t\n\t\t\t'},{id:"B118",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDamjanovic\n\t\t\t\t\t\t\tA. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGlaser\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKiecolt-Glaser\n\t\t\t\t\t\t\tJ. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNguyen\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaskowski\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZou\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeversdorf\n\t\t\t\t\t\t\tD. Q.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeng\n\t\t\t\t\t\t\tN. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tAccelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer’s disease patients\n\t\t\t\t\tJ Immunol\n\t\t\t\t\t179\n\t\t\t\t\t6\n\t\t\t\t\t4249\n\t\t\t\t\t4254\n\t\t\t\t\n\t\t\t'},{id:"B119",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmogorzewska\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Lange\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tRegulation of telomerase by telomeric proteins\n\t\t\t\t\tAnnu Rev Biochem\n\t\t\t\t\t73\n\t\t\t\t\t177\n\t\t\t\t\t208\n\t\t\t\t\n\t\t\t'},{id:"B120",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarley\n\t\t\t\t\t\t\tC. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFutcher\n\t\t\t\t\t\t\tA. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreider\n\t\t\t\t\t\t\tC. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1990\n\t\t\t\t\tTelomeres shorten during ageing of human fibroblasts\n\t\t\t\t\tNature\n\t\t\t\t\t345\n\t\t\t\t\t6274\n\t\t\t\t\t458\n\t\t\t\t\t460\n\t\t\t\t\n\t\t\t'},{id:"B121",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarley\n\t\t\t\t\t\t\tC. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tN. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tProwse\n\t\t\t\t\t\t\tK. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeinrich\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHirsch\n\t\t\t\t\t\t\tK. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWest\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBacchetti\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHirte\n\t\t\t\t\t\t\tH. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCounter\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreider\n\t\t\t\t\t\t\tC. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1994\n\t\t\t\t\tTelomerase, cell immortality, and cancer,\n\t\t\t\t\tCold Spring Harb Symp Quant Biol\n\t\t\t\t\t59\n\t\t\t\t\t307\n\t\t\t\t\t315\n\t\t\t\t\n\t\t\t'},{id:"B122",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCesare\n\t\t\t\t\t\t\tA.J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReddel\n\t\t\t\t\t\t\tR.R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tAlternative lengthening of telomeres: models, mechanisms and implications\n\t\t\t\t\tNat Rev Genet\n\t\t\t\t\t11\n\t\t\t\t\t5\n\t\t\t\t\t319\n\t\t\t\t\t330\n\t\t\t\t\n\t\t\t'},{id:"B123",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerdun\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarlseder\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tReplication and protection of telomeres\n\t\t\t\t\tNature\n\t\t\t\t\t447\n\t\t\t\t\t7147\n\t\t\t\t\t924\n\t\t\t\t\t931\n\t\t\t\t\n\t\t\t'},{id:"B124",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchulz\n\t\t\t\t\t\t\tV. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZakian\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOgburn\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Kay\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJarzebowicz\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdland\n\t\t\t\t\t\t\tS. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartin\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996\n\t\t\t\t\tAccelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells\n\t\t\t\t\tHum Genet\n\t\t\t\t\t97\n\t\t\t\t\t6\n\t\t\t\t\t750\n\t\t\t\t\t754\n\t\t\t\t\n\t\t\t'},{id:"B125",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaird\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavis\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRowson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJones\n\t\t\t\t\t\t\tC. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKipling\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tNormal telomere erosion rates at the single cell level in Werner syndrome fibroblast cells\n\t\t\t\t\tHum Mol Genet\n\t\t\t\t\t13\n\t\t\t\t\t14\n\t\t\t\t\t1515\n\t\t\t\t\t1524\n\t\t\t\t\n\t\t\t'},{id:"B126",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLombard\n\t\t\t\t\t\t\tD. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeard\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarciniak\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDausman\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBronson\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuhlmann\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLipman\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCurry\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharpe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJaenisch\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuarente\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tMutations in the WRN gene in mice accelerate mortality in a p53-null background\n\t\t\t\t\tMol Cell Biol\n\t\t\t\t\t20\n\t\t\t\t\t9\n\t\t\t\t\t3286\n\t\t\t\t\t3291\n\t\t\t\t\n\t\t\t'},{id:"B127",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChang\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tA mouse model of Werner Syndrome: what can it tell us about aging and cancer ?\n\t\t\t\t\tInt J Biochem Cell Biol\n\t\t\t\t\t37\n\t\t\t\t\t5\n\t\t\t\t\t991\n\t\t\t\t\t999\n\t\t\t\t\n\t\t\t'},{id:"B128",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKugan\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFurth\n\t\t\t\t\t\t\tE. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLombard\n\t\t\t\t\t\t\tD. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheung\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPak\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLuo\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPignolo\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Pinho\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuarente\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tF. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tTelomere shortening exposes functions for the mouse Werner and Bloom syndrome genes\n\t\t\t\t\tMol Cell Biol\n\t\t\t\t\t24\n\t\t\t\t\t19\n\t\t\t\t\t8437\n\t\t\t\t\t8446\n\t\t\t\t\n\t\t\t'},{id:"B129",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChang\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMultani\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCabrera\n\t\t\t\t\t\t\tN. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaylor\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaud\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLombard\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPathak\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuarente\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Pinho\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tEssential role of limiting telomeres in the pathogenesis of Werner syndrome\n\t\t\t\t\tNat Genet\n\t\t\t\t\t36\n\t\t\t\t\t8\n\t\t\t\t\t877\n\t\t\t\t\t882\n\t\t\t\t\n\t\t\t'},{id:"B130",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStavropoulos\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBradshaw\n\t\t\t\t\t\t\tP. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPasic\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTruong\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkura\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUngrin\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeyn\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tThe Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis\n\t\t\t\t\tHum Mol Genet\n\t\t\t\t\t11\n\t\t\t\t\t25\n\t\t\t\t\t3135\n\t\t\t\t\t3144\n\t\t\t\t\n\t\t\t'},{id:"B131",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLillard-Wetherell\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLangland\n\t\t\t\t\t\t\tG. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCombs\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBehbehani\n\t\t\t\t\t\t\tG. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchonberg\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerman\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTurchi\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGroden\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tAssociation and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2\n\t\t\t\t\tHum Mol Genet\n\t\t\t\t\t13\n\t\t\t\t\t17\n\t\t\t\t\t1919\n\t\t\t\t\t1932\n\t\t\t\t\n\t\t\t'},{id:"B132",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tTRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA\n\t\t\t\t\tOncogene\n\t\t\t\t\t23\n\t\t\t\t\t1\n\t\t\t\t\t149\n\t\t\t\t\t156\n\t\t\t\t\n\t\t\t'},{id:"B133",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobbe\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaine\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarrigan\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tTelomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t277\n\t\t\t\t\t43\n\t\t\t\t\t41110\n\t\t\t\t\t41119\n\t\t\t\t\n\t\t\t'},{id:"B134",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMason\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPodell\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLei\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCech\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tPOT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t280\n\t\t\t\t\t37\n\t\t\t\t\t32069\n\t\t\t\t\t32080\n\t\t\t\t\n\t\t\t'},{id:"B135",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNora\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuncher\n\t\t\t\t\t\t\tN. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tTelomeric protein TRF2 protects Holliday junctions with telomeric arms from displacement by the Werner syndrome helicase\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t38\n\t\t\t\t\t12\n\t\t\t\t\t3984\n\t\t\t\t\t3998\n\t\t\t\t\n\t\t\t'},{id:"B136",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKozak\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartin\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPennock\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tF. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tEvidence that a RecQ helicase slows senescence by resolving recombining telomeres\n\t\t\t\t\tPLoS Biol\n\t\t\t\t\t5\n\t\t\t\t\t6\n\t\t\t\t\te160\n\t\t\t\t\n\t\t\t'},{id:"B137",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDuquette\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanda\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVincent\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaylor\n\t\t\t\t\t\t\tA. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaizels\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIntracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t18\n\t\t\t\t\t13\n\t\t\t\t\t1618\n\t\t\t\t\t1629\n\t\t\t\t\n\t\t\t'},{id:"B138",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZaug\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPodell\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCech\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tHuman POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t102\n\t\t\t\t\t31\n\t\t\t\t\t10864\n\t\t\t\t\t10869\n\t\t\t\t\n\t\t\t'},{id:"B139",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMohaghegh\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tDNA helicase deficiencies associated with cancer predisposition and premature ageing disorders\n\t\t\t\t\tHum Mol Genet\n\t\t\t\t\t10\n\t\t\t\t\t7\n\t\t\t\t\t741\n\t\t\t\t\t746\n\t\t\t\t\n\t\t\t'},{id:"B140",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaine\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeidman\n\t\t\t\t\t\t\tM. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tCoordinate action of the helicase and 3’ to 5’ exonuclease of Werner syndrome protein\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t276\n\t\t\t\t\t48\n\t\t\t\t\t44677\n\t\t\t\t\t44687\n\t\t\t\t\n\t\t\t'},{id:"B141",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKusumoto-Matsuo\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamsden\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTahara\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tCooperation of DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops\n\t\t\t\t\tAging (Albany NY)\n\t\t\t\t\t2\n\t\t\t\t\t5\n\t\t\t\t\t274\n\t\t\t\t\t284\n\t\t\t\t\n\t\t\t'},{id:"B142",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrabbe\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerdun\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHaggblom\n\t\t\t\t\t\t\tC. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarlseder\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tDefective telomere lagging strand synthesis in cells lacking WRN helicase activity\n\t\t\t\t\tScience\n\t\t\t\t\t306\n\t\t\t\t\t5703\n\t\t\t\t\t1951\n\t\t\t\t\t1953\n\t\t\t\t\n\t\t\t'},{id:"B143",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDewar\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLydall\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tPif1- and Exo1-dependent nucleases coordinate checkpoint activation following telomere uncapping\n\t\t\t\t\tEMBO J\n\t\t\t\t\t29\n\t\t\t\t\t23\n\t\t\t\t\t4020\n\t\t\t\t\t4034\n\t\t\t\t\n\t\t\t'},{id:"B144",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarefield\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarlseder\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tThe BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t40\n\t\t\t\t\t15\n\t\t\t\t\t7358\n\t\t\t\t\t7367\n\t\t\t\t\n\t\t\t'},{id:"B145",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tTelomere ResQue and preservation--roles for the Werner syndrome protein and other RecQ helicases\n\t\t\t\t\tMech Ageing Dev\n\t\t\t\t\t129\n\t\t\t\t\t1-2\n\t\t\t\t\t79\n\t\t\t\t\t90\n\t\t\t\t\n\t\t\t'},{id:"B146",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArnoult\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaintome\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOurliac-Garnier\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRiou\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLondono-Vallejo\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tHuman POT1 is required for efficient telomere C-rich strand replication in the absence of WRN\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t23\n\t\t\t\t\t24\n\t\t\t\t\t2915\n\t\t\t\t\t2924\n\t\t\t\t\n\t\t\t'},{id:"B147",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchulz\n\t\t\t\t\t\t\tV.P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZakian\n\t\t\t\t\t\t\tV.A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994\n\t\t\t\t\tThe saccharomyces PIF1 DNA helicase inhibits telomere elongation and de novo telomere formation\n\t\t\t\t\tCell\n\t\t\t\t\t76\n\t\t\t\t\t1\n\t\t\t\t\t145\n\t\t\t\t\t155\n\t\t\t\t\n\t\t\t'},{id:"B148",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeorge\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWen\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGriffiths\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGanesh\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeuth\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSanders\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tHuman Pif1 helicase unwinds synthetic DNA structures resembling stalled DNA replication forks\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t37\n\t\t\t\t\t19\n\t\t\t\t\t6491\n\t\t\t\t\t6502\n\t\t\t\t\n\t\t\t'},{id:"B149",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaeschke\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCapra\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZakian\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tDNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase\n\t\t\t\t\tCell\n\t\t\t\t\t145\n\t\t\t\t\t5\n\t\t\t\t\t678\n\t\t\t\t\t691\n\t\t\t\t\n\t\t\t'},{id:"B150",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheung\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchertzer\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRose\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLansdorp\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tDisruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA\n\t\t\t\t\tNat Genet\n\t\t\t\t\t31\n\t\t\t\t\t4\n\t\t\t\t\t405\n\t\t\t\t\t409\n\t\t\t\t\n\t\t\t'},{id:"B151",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVallur\n\t\t\t\t\t\t\tA. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaizels\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tDistinct activities of exonuclease 1 and flap endonuclease 1 at telomeric g4 DNA\n\t\t\t\t\tPLoS One\n\t\t\t\t\t5\n\t\t\t\t\t1\n\t\t\t\t\te8908\n\t\t\t\t\n\t\t\t'},{id:"B152",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEller\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanna\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBackvall\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGilchrest\n\t\t\t\t\t\t\tB. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tA role for WRN in telomere-based DNA damage responses\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t103\n\t\t\t\t\t41\n\t\t\t\t\t15073\n\t\t\t\t\t15078\n\t\t\t\t\n\t\t\t'},{id:"B153",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJog\n\t\t\t\t\t\t\tS. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReddy\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tComai\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tWRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening\n\t\t\t\t\tMol Cell Biol\n\t\t\t\t\t28\n\t\t\t\t\t6\n\t\t\t\t\t1892\n\t\t\t\t\t1904\n\t\t\t\t\n\t\t\t'},{id:"B154",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReddy\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tComai\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tProcessing of human telomeres by the Werner syndrome protein\n\t\t\t\t\tCell Cycle\n\t\t\t\t\t9\n\t\t\t\t\t16\n\t\t\t\t\t3137\n\t\t\t\t\t3138\n\t\t\t\t\n\t\t\t'},{id:"B155",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReddy\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tComai\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tSequence-specific processing of telomeric 3’ overhangs by the Werner syndrome protein exonuclease activity\n\t\t\t\t\tAging (Albany NY)\n\t\t\t\t\t1\n\t\t\t\t\t3\n\t\t\t\t\t289\n\t\t\t\t\t302\n\t\t\t\t\n\t\t\t'},{id:"B156",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTheodore\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tThe Werner syndrome helicase/exonuclease (WRN) disrupts and degrades D-loops in vitro\n\t\t\t\t\tBiochemistry\n\t\t\t\t\t41\n\t\t\t\t\t46\n\t\t\t\t\t13483\n\t\t\t\t\t13488\n\t\t\t\t\n\t\t\t'},{id:"B157",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tF. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarciniak\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Vey\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStewart\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHahn\n\t\t\t\t\t\t\tW. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuarente\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tThe Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase\n\t\t\t\t\tEMBO J\n\t\t\t\t\t20\n\t\t\t\t\t4\n\t\t\t\t\t905\n\t\t\t\t\t913\n\t\t\t\t\n\t\t\t'},{id:"B158",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCohen\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSinclair\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\tRecombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase\n\t\t\t\t\tProc Natl Acad Sci U S A\n\t\t\t\t\t6\n\t\t\t\t\t3174\n\t\t\t\t\t3179\n\t\t\t\t\t2001\n\t\t\t\t\n\t\t\t'},{id:"B159",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNeumann\n\t\t\t\t\t\t\tA.A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReddel\n\t\t\t\t\t\t\tR.R\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tTelomere maintenance and cancer-- look, no telomerase\n\t\t\t\t\tNat Rev Cancer\n\t\t\t\t\t2\n\t\t\t\t\t11\n\t\t\t\t\t879\n\t\t\t\t\t884\n\t\t\t\t\n\t\t\t'},{id:"B160",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDunham\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNeumann\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFasching\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReddel\n\t\t\t\t\t\t\tR. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tTelomere maintenance by recombination in human cells\n\t\t\t\t\tNat Genet\n\t\t\t\t\t26\n\t\t\t\t\t4\n\t\t\t\t\t447\n\t\t\t\t\t450\n\t\t\t\t\n\t\t\t'},{id:"B161",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHickson\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tRecQ helicases: caretakers of the genome\n\t\t\t\t\tNat Rev Cancer\n\t\t\t\t\t3\n\t\t\t\t\t3\n\t\t\t\t\t169\n\t\t\t\t\t178\n\t\t\t\t\n\t\t\t'},{id:"B162",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBailey\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCornforth\n\t\t\t\t\t\t\tM. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUllrich\n\t\t\t\t\t\t\tR. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoodwin\n\t\t\t\t\t\t\tE. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tDysfunctional mammalian telomeres join with DNA double-strand breaks\n\t\t\t\t\tDNA Repair (Amst)\n\t\t\t\t\t3\n\t\t\t\t\t4\n\t\t\t\t\t349\n\t\t\t\t\t357\n\t\t\t\t\n\t\t\t'},{id:"B163",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBailey\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrenneman\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoodwin\n\t\t\t\t\t\t\tE. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tFrequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t32\n\t\t\t\t\t12\n\t\t\t\t\t3743\n\t\t\t\t\t3751\n\t\t\t\t\n\t\t\t'},{id:"B164",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaud\n\t\t\t\t\t\t\tP. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMultani\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBailey\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMa\n\t\t\t\t\t\t\tKingsley\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLebel\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPathak\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Pinho\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChang\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tElevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t19\n\t\t\t\t\t21\n\t\t\t\t\t2560\n\t\t\t\t\t2570\n\t\t\t\t\n\t\t\t'},{id:"B165",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCelli\n\t\t\t\t\t\t\tG. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDenchi\n\t\t\t\t\t\t\tE. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Lange\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\tKu70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination\n\t\t\t\t\tNat Cell Biol 8\n\t\t\t\t\t8\n\t\t\t\t\t885\n\t\t\t\t\t890\n\t\t\t\t\t2006\n\t\t\t\t\n\t\t\t'},{id:"B166",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDanzy\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tOxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t33\n\t\t\t\t\t4\n\t\t\t\t\t1230\n\t\t\t\t\t1239\n\t\t\t\t\n\t\t\t'},{id:"B167",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCooper\n\t\t\t\t\t\t\tM. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMachwe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrren\n\t\t\t\t\t\t\tD. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrosh\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamsden\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tKu complex interacts with and stimulates the Werner protein\n\t\t\t\t\tGenes Dev 14\n\t\t\t\t\t8\n\t\t\t\t\t907\n\t\t\t\t\t912\n\t\t\t\t\n\t\t\t'},{id:"B168",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPetersen\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaretzki\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon Zglinicki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tPreferential accumulation of single-stranded regions in telomeres of human fibroblasts\n\t\t\t\t\tExp Cell Res\n\t\t\t\t\t239\n\t\t\t\t\t1\n\t\t\t\t\t152\n\t\t\t\t\t160\n\t\t\t\t\n\t\t\t'},{id:"B169",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZglinicki\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaretzki\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLadhoff\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\td’Adda di\n\t\t\t\t\t\t\tFagagna.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tS. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tHuman cell senescence as a DNA damage response\n\t\t\t\t\tMech Ageing Dev\n\t\t\t\t\t126\n\t\t\t\t\t1\n\t\t\t\t\t111\n\t\t\t\t\t117\n\t\t\t\t\n\t\t\t'},{id:"B170",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPassos\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaretzki\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAhmed\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNelson\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRichter\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeters\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWappler\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBirket\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarold\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchaeuble\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBirch-Machin\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKirkwood\n\t\t\t\t\t\t\tT. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon Zglinicki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tMitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence\n\t\t\t\t\tPLoS Biol\n\t\t\t\t\t5\n\t\t\t\t\t5\n\t\t\t\t\te110\n\t\t\t\t\n\t\t\t'},{id:"B171",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPassos\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaretzki\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon Zglinicki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tDNA damage in telomeres and mitochondria during cellular senescence: is there a connection?\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t35\n\t\t\t\t\t22\n\t\t\t\t\t7505\n\t\t\t\t\t7513\n\t\t\t\t\n\t\t\t'},{id:"B172",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarlseder\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmogorzewska\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Lange\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tSenescence induced by altered telomere state, not telomere loss\n\t\t\t\t\tScience\n\t\t\t\t\t295\n\t\t\t\t\t5564\n\t\t\t\t\t2446\n\t\t\t\t\t2449\n\t\t\t\t\n\t\t\t'},{id:"B173",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarrigan\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t3rd Prasad\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMay\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tThe Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta\n\t\t\t\t\tNucleic Acids Res\n\t\t\t\t\t34\n\t\t\t\t\t2\n\t\t\t\t\t745\n\t\t\t\t\t754\n\t\t\t\t\n\t\t\t'},{id:"B174",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarrigan\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobbe\n\t\t\t\t\t\t\tP. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKedar\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrasad\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tThe Werner syndrome protein stimulates DNA polymerase beta strand displacement synthesis via its helicase activity\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t278\n\t\t\t\t\t25\n\t\t\t\t\t22686\n\t\t\t\t\t22695\n\t\t\t\t\n\t\t\t'},{id:"B175",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPagano\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZatterale\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDegan\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\td’Ischia\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKelly\n\t\t\t\t\t\t\tF. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPallardo\n\t\t\t\t\t\t\tF. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKodama\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tMultiple involvement of oxidative stress in Werner syndrome phenotype\n\t\t\t\t\tBiogerontology\n\t\t\t\t\t6\n\t\t\t\t\t4\n\t\t\t\t\t233\n\t\t\t\t\t243\n\t\t\t\t\n\t\t\t'},{id:"B176",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLabbe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTuraga\n\t\t\t\t\t\t\tR. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaquet\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarand\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLebel\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tExpression profiling of mouse embryonic fibroblasts with a deletion in the helicase domain of the Werner Syndrome gene homologue treated with hydrogen peroxide\n\t\t\t\t\tBMC Genomics\n\t\t\t\t\t11\n\t\t\t\t\t127\n\t\t\t\t\n\t\t\t'},{id:"B177",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGhosh\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRossi\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAulds\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCroteau\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tTelomeric D-loops containing 8-oxo-2’-deoxyguanosine are preferred substrates for Werner and Bloom syndrome helicases and are bound by POT1\n\t\t\t\t\tJ Biol Chem\n\t\t\t\t\t284\n\t\t\t\t\t45\n\t\t\t\t\t31074\n\t\t\t\t\t31084\n\t\t\t\t\n\t\t\t'},{id:"B178",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuftuoglu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWong\n\t\t\t\t\t\t\tH. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImam\n\t\t\t\t\t\t\tS. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t3rd Bohr\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tTelomere repeat binding factor 2 interacts with base excision repair proteins and stimulates DNA synthesis by DNA polymerase beta\n\t\t\t\t\tCancer Res\n\t\t\t\t\t66\n\t\t\t\t\t1\n\t\t\t\t\t113\n\t\t\t\t\t124\n\t\t\t\t\n\t\t\t'},{id:"B179",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalakrishnan\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuncher\n\t\t\t\t\t\t\tN. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOpresko\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBambara\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tTelomere proteins POT1, TRF1 and TRF2 augment long-patch base excision repair in vitro\n\t\t\t\t\tCell Cycle\n\t\t\t\t\n\t\t\t'}],footnotes:[{id:"fn1",explanation:" RTS is found in a subset of patients with RECQL4 mutation; different mutations in the same gene give rise to RAPADILLINO syndrome [1] "},{id:"fn2",explanation:"Many other proteins also bind to PCNA in this manner – some regulate PCNA’s activity (e.g. p21) [58] while others are regulated by such binding (e.g. Cdt1 degradation is PIP-dependent) [59]."},{id:"fn3",explanation:"ALT = alternative lengthening of telomeres"},{id:"fn4",explanation:"8-oxoG is a common product of oxidative attack of DNA"}],contributors:[{corresp:"yes",contributorFullName:"Lynne S. Cox",address:"Lynne.cox@bioch.ox.ac.uk",affiliation:'
Department of Biochemistry, University of Oxford, South Parks Road, Oxford
'},{corresp:null,contributorFullName:"Penelope A. Mason",address:null,affiliation:'
Department of Biochemistry, University of Oxford, South Parks Road, Oxford
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Brandt-Rauf, Yongliang Li, Changmin Long and Regina\nMonaco",authors:[{id:"160455",title:"Prof.",name:"Paul",middleName:null,surname:"Brandt-Rauf",fullName:"Paul Brandt-Rauf",slug:"paul-brandt-rauf"}]},{id:"44596",title:"Aspects of DNA Damage from Internal Radionuclides",slug:"aspects-of-dna-damage-from-internal-radionuclides",signatures:"Christopher Busby",authors:[{id:"157686",title:"Prof.",name:"Christopher",middleName:null,surname:"Busby",fullName:"Christopher Busby",slug:"christopher-busby"}]},{id:"44527",title:"Radiosensitization Strategies Through Modification of DNA Double-Strand Break Repair",slug:"radiosensitization-strategies-through-modification-of-dna-double-strand-break-repair",signatures:"Yoshihisa Matsumoto, Shoji Imamichi, Mikoto Fukuchi, Sicheng Liu,\nWanotayan Rujira, Shingo Kuniyoshi, Kazuki Yoshida, Yasuhiro Mae\nand Mukesh Kumar Sharma",authors:[{id:"42493",title:"Dr.",name:"Yoshihisa",middleName:null,surname:"Matsumoto",fullName:"Yoshihisa Matsumoto",slug:"yoshihisa-matsumoto"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"63441",title:"Stress Corrosion Cracking Damages",doi:"10.5772/intechopen.80826",slug:"stress-corrosion-cracking-damages",body:'
1. Introduction
Stress corrosion cracking (SCC) in chemical, petrochemical, and power plant industries is an insidious form of corrosion, which causes a lot of financial losses and human damages [1, 2, 3, 4, 5]. This phenomenon is associated with a combination of tensile stress, environment, and some metallurgical conditions as described in Figure 1.
Figure 1.
The essential requirements for SCC.
During stress corrosion cracking, the metal or alloy is virtually unattacked over most of its surface, while fine and branch cracks progress through the bulk of material [6]. It is shown in Figure 2. This cracking phenomenon has serious consequences since it can occur under stresses much lower than design stresses and lead the equipment and structures to premature failures [7, 8, 9, 10, 11].
Figure 2.
Crack development in carbon steel exposed to nitrate solution.
Stress corrosion cracking starts from corrosion sites at the material surfaces and progresses into a brittle manner. The process of cracking is not strictly a mechanical process, as the corrosivity of the environment strongly affects the fracture mode. Both intergranular and transgranular stress corrosion cracking are observed. Intergranular cracking proceeds along grain boundaries, while transgranular cracking advances without apparent preference for boundaries [12]. An example of stress corrosion cracking in which the crack has progressed in both intergranular and transgranular paths is shown in Figure 3. The development mode of cracking depends on the composition and microstructure of the material and environment.
Figure 3.
Intergranular and transgranular stress corrosion cracking of the AISI 316L stainless steel at polythionic acid environment [8].
In this chapter, the conditions for the occurrence of SCC are first introduced. Then, the stress corrosion cracking mechanism for various materials in conditions that are susceptible is discussed in detail. The design of industrial structures and components is usually based on tensile properties, which have many disadvantages. So, the science of fracture mechanics applies in the situations prone to SCC because of the inevitability of manufacturing and service defects in materials and for considering the role of such imperfections. Methods of prevention based on corrosion science and empirical data are presented. Finally, practical examples are given to better understand the issue.
2. Requirements for SCC
Not all metal-environment combinations are susceptible to cracking. In other words, the environment for occurrences of SCC for each metal or alloys is specific. Also, the resources of stress for each case of failure may be different.
2.1 Materials
2.1.1 Stainless steels
Austenitic stainless steels suffer from SCC in chlorides, caustic, and polythionic acid. When austenitic stainless steels with sufficient carbon content (more than 0.03 wt.%) are heated in the range of 415–850°C, their microstructure becomes susceptible to precipitation of chromium carbides (M23C6) along grain boundaries known as sensitization [9, 12, 13]. Formation of Cr-rich carbides along grain boundaries may drastically deplete free chromium content in the area adjacent to the grain boundaries and render them susceptible to rapid preferential dissolution. Sensitized steels are most susceptible; the stress corrosion cracking of nonsensitized steels is also observed [14, 15]. Dissolution of grain boundaries in some corrosive environments aside from tensile stress led these types of materials to SCC.
2.1.2 Copper and copper alloys
Seasonal cracking of brass in the rainy season in an ammoniacal environment is another classical example of SCC. This was first identified on the brass cartridge used by the British Army in India. Since it is usually identified during the rainy season, it is also called seasonal cracking [12]. Alpha brass is an alloy of Cu-Zn. It can crack either intergranularly or transgranularly in nontarnishing ammonia solutions, depending on its zinc content [16, 17, 18]. Transgranular stress corrosion cracking, TGSCC, is observed in alloys with 20 or 30% Zn but not in alloys with 0.5 or 10% Zn [19, 20]. Stress corrosion cracking of Cu-Zn and Cu-A1 alloys in cuprous ammonia solutions can only occur when the parting limits for dealloying are exceeded. The parting limits are about 14 and 18 a/o for Cu-A1 and Cu-Zn, respectively [21]. Cu-A1 and Cu-Ga alloys have shown similar behaviors [19, 22].
2.1.3 Aluminum and aluminum alloys
Aluminum and all its alloys can fail by cracking along grain boundaries when simultaneously exposed to specific environments and stresses of sufficient magnitude [23, 24]. Of eight series of aluminum alloys, 2xxx, 5xxx, and 7xxx aluminum alloys are susceptible to SCC. Among them, 7xxx series aluminum alloys have a specific application in aerospace, military, and structural industries due to superior mechanical properties. In these high-strength 7xxx aluminum alloys, SCC plays a vital factor of consideration, as these failures are catastrophic during the service [25].
2.1.4 Carbon steels
Carbon and low alloy steels have shown SCC in a wide range of environments that tend to form a protective passive or oxide film [26, 27, 28, 29, 30]. The environments that would passivate carbon steels have been found to cause SCC, including strong caustic solutions, phosphates, nitrates, carbonates, ethanol, and high-temperature water. The problems are important for both economic and safety reasons, due to the extensive use of carbon steels [31]. For example, nitrate cracking in an ammonium nitrate plant caused by catastrophic failures and a lot of financial losses. Caustic cracking of steam-generating boilers made of low alloy steels was a serious problem, which led an ammonia plant to repeated emergency shutdowns.
2.1.5 Titanium alloys
Stress corrosion cracking may be a problem whenever certain high-strength titanium alloys are exposed to aqueous and certain solvent environments [32, 33, 34, 35, 36]. For the first time, SCC of titanium was reported by Kiefer and Harple who describe the cracking phenomena with commercially pure titanium in red fuming nitric acid [37]. Hot salt cracking of titanium alloys was reported in turbine blades that operate at high temperature in the mid-1950s. The subject became very active in the early 1960s because of the SCC problem connected to these alloys in a transportation program [38].The first known report of stress corrosion cracking of titanium alloys in room temperature aqueous environments was that of Brown. He found that titanium alloys, 8% aluminum–1% molybdenum–1% vanadium alloy (Ti, 8–1–1), were susceptible to SCC in seawater [38].
2.2 Environments
Another requirement for SCC to occur is a corrosive environment. The environments for SCC are specific because not all environments promote SCC. For those alloys that develop a protective film, an aggressive ion is required to promote SCC. The aggressive media to passive layer of stainless steels are chlorides, caustic, and polythionic acid. The austenitic stainless steel series 300 is more susceptible in an environment containing chlorides. Chlorides will not cause SCC unless an aqueous phase is present. It appears that stress corrosion cracking in austenitic stainless steels in the presence of chlorides proceeds transgranularly and usually occurs at temperature above 70°C [39, 40]. Cases of SCC due to chlorides have been experienced at ambient temperatures on parts that were subjected to heavy machining [41, 42]. Caustic embrittlement or stress corrosion cracking in caustic environment is another serious problem in austenitic stainless steels and causes many explosions and other types of failures in steam boiler and super heater components [9, 43, 44, 45]. Caustic cracking failures frequently originate in a welding area, which is intergranular, and a very concentrated caustic solution is usually necessary [40]. Polythionic acid is another environment, which causes SCC in austenitic stainless steels. Sulfur in feed gas in chemical and petrochemical plants led to formation of polythionic acid (H2SxO6, x = 2–5), which aside from moisture also induced intergranular stress corrosion cracking in austenitic stainless steels [46, 47]. Well-known specific environments for the stress corrosion cracking in Al alloys include water vapor, aqueous solutions, organic liquids, and liquid metals [48]. The SCC of Ti alloys in aqueous chloride and methanolic chloride environments at ambient temperatures has been widely reported [49]. The summary of environments that cause SCC in mostly used alloys is presented in Table 1.
Metal
Environment
Al alloys
NaCl-H2O2 solutions
NaCl solutions
Seawater
Copper alloys
Ammonia vapor and solutions
Amines
Water or water vapor
Gold alloys
FeCl3 solutions
Acetic acid-salt solutions
Inconel
Caustic soda solutions
Lead
Lead acetate solutions
Magnesium alloys
NaCl-Na2CrO4 solutions
Rural and coastal atmospheres
Seawater
Distilled water
Nickel
Fused caustic soda
Steels
NaOH solutions
NaOH-Na2SiO4 solutions
Calcium, ammonium, and sodium nitrite solutions
Mixed acids (H2SO4-HNO3)
Acidic H2S solutions
Seawater
Carbonate-bicarbonate solutions
Stainless steels
Acidic chloride solutions
NaCl-H2O2 solutions
Seawater
H2S
NaOH-H2S solutions
Condensing steam from chloride waters
Titanium alloys
Red fuming nitric acid
Seawater
Methanol-HCl
Table 1.
Summary of some environments caused by SCC on different alloys.
The stress in the form of tensile (not compressive) plays a key role in the SCC fracture processes. In fact, SCC would never have occurred in the absence of stress. The required tensile stresses may be in the form of directly applied stresses, thermal, in the form of residual stresses, or a combination of all [8, 50]:
σ=σapplied+σthermal+σresidualE1
For SCC to occur alone by applied stress, it must have a very high magnitude. The welding and mechanical residual stresses are the main sources of stress attributed to the stress corrosion cracking. The welding residual stress is produced as a result of nonuniform temperature changes during welding operation and can be calculated from thermal strain vectors.
The thermal strain vector, Δεth, is formulated by a temperature-dependent differential expansion coefficient (°/c) as follows [2]:
Δεth=αΔTE2
in which Δεth is the variation of strain, α is the thermal expansion of material, and ΔT is the temperature change.
The operational thermal stress can also be calculated from Eq. 2. Mechanical workings such as cold deformation and forming, machining, and grinding are the other sources, which introduce residual stresses [8, 51].
3. Stress corrosion cracking mechanism
Extensive investigations have been devoted to find mechanisms of SCC for different materials and environments. An SCC failure illustrates the combined effects of mechanical, physical, and chemical/electrochemical factors causing the separation of metal bonds at the crack tip, thereby advancing the crack. Three mechanisms for SCC have been proposed through the investigations [52]:
3.1 Pre-existing active path mechanism
This model supposes that there are pre-existing paths in an alloy that is susceptible to anodic dissolution. Because of precipitation or solute segregation of impurities like sulfur, phosphorus, and chromium carbides, the electrochemical properties of the matrix and segregates are changed. The area adjacent to the grain boundaries is depleted from one or more alloying elements, and so under such conditions, localized galvanic cells are created (Figure 4). Since precipitation or segregation is generally anodic to the matrix of the grains, dissolution under an anodic reaction occurs and provides active path for localized corrosions [53]. Also, the removal of the protective film at the pre-existing crack tips by plastic deformation would facilitate the onset of localized corrosion.
Figure 4.
Galvanic cell mechanism [52].
3.2 Strain-generated active path mechanisms
This mechanism has been extensively studied in stress corrosion cracking of alpha brass in ammoniacal environment and also proposed for caustic cracking of boiler steel. The model is based on the idea of a strain-induced rupture of the protective film, and so plastic strains play a main role in failure processes [52, 55]. The theory assumes the existence of a passivation film on a metal surface. The passivation film protects the underlying metal against corrosive agents. The passivation film is ruptured by plastic strain due to mechanical workings. After the film is ruptured, the bare metal is exposed to the corrosive environment. The processes of disruptive strain (disruption of protective film) and film formation (due to repassivation) have occurred and alternate with each other. The crack propagates when the rate of rupture of oxide film is higher than the rate of repassivation of the film [52]. The mechanism is shown in Figure 5.
Figure 5.
Strain-generated active path mechanisms. (A) Film rupture model and (B) slip-step dissolution model [52].
3.3 Adsorption-related phenomenon
This model is based on the effects of environmental species on interatomic bond strength. The theoretical fracture stress required to separate two layers of atoms of spacing b is given by [56].
σf=Eγsb1/2E3
where E is the Young modulus, γ is the surface energy, and b is the spacing between atoms.
This theory implies that if surface energy is reduced, then σf will also be reduced. In corrosive environments, aggressive agents are present and they are absorbed at the crack tips, the surface energy is effectively lowered, and fracture takes place in stress much lower than design stress [52].
4. Application of fracture mechanics
The design of steel structure and component based on tensile properties has many disadvantages that do not take into account the role of imperfections. Fracture mechanic introduces another material characteristic, namely, fracture toughness, KIC, which considered the role of cracks and imperfection in the form of cracks in designs. In its simplest form [57].
KIC=σπaE4
where σ is the design stress and a is the size of an existing crack.
According to this equation, fracture occurs when stress intensity factor, Kt, on the crack tip is equal to KIC. This applies for the propagation of cracks due to mechanical loadings. For the structure parts exposed to corrosive environments, the situation is quietly different. The corrosive agents caused a significant drop in the load capacity and the fracture toughness of the metals. This is typically shown in Figure 6. As outlined in the diagram, designs of structures in the corrosive environment based on KIc led the component to failure in a short period of time. Therefore, in these situations, KIc should be replaced with KIscc, which is the threshold value for SCC [12]. This means that in the corrosive environment, the load capacity must be significantly lower than the clean environments. The use of fracture mechanics for high-strength low alloy steels is responsive, but for austenitic steels with branch cracks, the subject should be treated with caution [12].
Figure 6.
Effects of corrosive environment on fracture toughness [12].
5. Prevention
Since the exact mechanism of SCC has not been completely understood, prevention methods are either general or empirical in nature. Appropriate strategy should be done in order to minimize this problem to ensure not only the safety of human life but also the safety of cost. The following general methods are recommended to overcome the SCC problems [12, 52, 58, 59]:
Lowering the tensile stress in the welded component using post weld heat treatment. The post weld heat treatment reduced or eliminated residual stress on surface and through the bulk of material. Plan and low alloy steels may be a stress relief at 1100–1200°F. The range of residual stress relief temperature for austenitic stainless steels is from 1500 to 1700°F. Reduction of tensile stresses by shot peening is also recommended. Shot peening introduces surface compressive stresses.
Eliminating aggressive agents from the environment by, for example, degasification, demineralization, or distillation.
Changing the alloy is one possible solution if neither the environment nor stress can be changed. For example, it is a common practice to use Inconel (raising the nickel content) when typ. 304 stainless steel is not satisfactory.
Applying cathodic protection: impressed current cathodic protection system has been successfully used to prevent SCC of steels.
Adding inhibitors to the system if feasible: high concentrations of phosphate have been successfully used.
Coatings are sometimes used, and they depend on keeping the environment away from the metal.
6. Failure case studies
6.1 Case 1: stress corrosion cracking of a circulation water heater tube sheet [8]
After only 3 years’ service of a circulation water heater (heat exchanger), it has been shown to sever leakage and has led a methanol plant to emergency shutdown. An on-site investigation revealed extensive cracking initiated at weld area and through the tube sheet holes as it is shown in Figure 7.
Figure 7.
Failed area (a) cracks extending in the weld joint of tube sheet to plugs and (b) branched cracks in the surface of the tube sheet and through the holes [8].
6.1.1 Material and environment
The circulation water heater is a vertical U-type heat exchanger made of austenitic stainless steels. The equipment used to decline reforms gas temperature in a methanol plant. The hot reformed gas at approximately 385°C entered the tubes and is cooled down to 168°C by exchanging the heat with processed water in the shell. The gases that flow through the tubes are mainly CO2, CO, H2, CH4, and N2 and at a pressure of 3.9 MPa. At the shell cooling process, water flows with about 6 MPa pressure.
6.1.2 Cause
Deposits had formed on top of the tube sheet due to shutdown errors. AISI 316L materials overheated in service because of the insulation role of the deposits. Material sensitization occurs since overheating. The presence of sulfur in the process gas aside from moisture formed polythionic acid during shutdowns. Residual stress produced by heavy machining and welding aside from operational thermal stress provided tensile stress, which is needed for SCC. Stress corrosion cracking is induced by polythionic acid. Concentrated water with other aggressive agents such as caustic and chlorides leaked through the cracks aid the failures.
6.1.3 Prevention
Cleaning of the shell by demineralized water after each shut down in order to prevent the forming of insulating deposits above the tube sheet
Reduction of sulfur in feeding gas
Reduction of caustic and chlorides in processed water
6.2 Case 2: failure of an austenitic stainless steel tubes in a gas-fired steam heater [9]
Carryover of caustic soda (NaOH) in the steam path caused catastrophic failure of superheater stainless steel tubes in a gas-fired heater and led to an unexpected shutdown after just 5 months of continuous service following the start of production. The failure areas are shown in Figure 8. Three types of cracks are identified in various regions of the tube: circumferential cracks adjacent to the seam weld, circumferential cracks at the ribbon of the seam weld, and longitudinal cracks on the U-bend. The path of cracks was complex on the surface or in the bulk metal; all had nucleated from inside the tubes. A visual inspection revealed a white deposit, high in sodium, around the cracks on the surface of the tubes.
Figure 8.
(a and b) Circumferential cracks adjacent to the seam weld, (c and d) circumferential cracks at the ribbon of seam weld, and (e) longitudinal cracks on the U-bend [9].
6.2.1 Material and environment
The superheater tube material was made of AISI 304H austenitic stainless steel material.
The gas-fired steam heater (FH) generates high-pressure (HP) steam for turbines for the processing of methanol. Demineralized water for the boiler and subsequent steam path is prepared in the water treatment unit. Caustic soda is injected to demineralized water for pH control. The water is transferred to the preheat exchangers, is converted to saturated high-pressure steam at 325°C and 119 MPa, and is sent to the FH. Through the FH tubes, saturated steam converted to supersaturate steam at a temperature of 505°C and pressure of 119 MPa.
6.2.2 Cause
The main cause of crack initiation was the increase of pH due to the rise of caustic concentration in condensed drops. Sensitized austenite grains caused by chromium carbide depletion adjacent to the grain boundaries were attacked by concentrated caustic in the HAZ metal and U-bend area and led the heater to the caustic SCC failure.
6.2.3 Prevention
Using A335 Grade P9, a low alloy steel tube shows higher resistance to SCC than AISI 304H stainless steel
Proper discharge of the tubes during shutdowns to prevent the formation of the concentrated deposits of caustic through the tubes
6.3 Case 3: failures of brass condenser tubes [60]
After a general overhaul of a thermal power plant in Serbia in November 2014, failure of hundreds of brass condenser tubes occurred during the hydrostatic test. Also, it was noted that some backing plates had fallen off from the tubes before this test. Fracture is observed only in condenser tubes of brass, as can be seen in Figure 9.
Figure 9.
Failure of brass condenser tubes near joining location with backing plate.
6.3.1 Material and environment
The failed tube material of the condenser was made of brass CuZn28Sn1 (admiralty brass). The cooling water (roughly filtered river water) flows through the tubes, while the hot steam flows around the tubes.
6.3.2 Cause
Analysis of fracture surfaces using scanning electron microscopy (SEM) has shown the brittle transgranular fracture due to the occurrence of SCC. The condenser tubes are made of brass CuZn28Sn1. Ammonia and other nitrogen compounds in the cooling water through the tubes were found. These compounds are specific agents that cause stress corrosion cracking (SCC) in brass. In the joining region of condenser tubes to backing plates, there are residual tensile stresses. During the floods in May 2014, there was an increase in the concentration of ammonia and other nitrogen compounds in the river cooling water flowing through the condenser tubes. Failure of brass condenser tubes occurred due to SCC, because the necessary conditions for the SCC occurrence were fulfilled.
6.3.3 Prevention
The risk of SCC in brass condenser tubes can be reduced if specific substances responsible for SCC occurrence are removed, as much as possible. This can be achieved by cleaning and drying the tubes immediately after the operation delay of the power plant.
Another way to reduce the risk of SCC occurrence in condenser tubes is the replacement of existing tubes (made of brass CuZn28Sn1, very susceptible to SCC) with tubes made of alloys of greater resistance to SCC, such as copper-nickel alloys or Bi-brass alloys [61].
7. Conclusion
Stress corrosion cracking is one of the main causes of unforeseen and dangerous destruction of industrial plants. The sensitized material, certain environments, and stress are three factors necessary for the occurrence of these types of failures. The environment prone to the cracking for each metal or alloy is specific because not all environments promote the SCC. Austenitic stainless steels suffer from SCC in chlorides, caustic, and polythionic acid. Copper alloys corrode in ammonia-containing environments. Well-known specific environments for the stress corrosion cracking in Al alloys include water vapor, aqueous solutions, organic liquids, and liquid metals. The SCC of Ti alloys in aqueous chloride and methanolic chloride environments has been widely reported. The tensile stress plays a key role in the stress corrosion cracking phenomenon. The required tensile stresses may be in the form of directly applied stresses, thermal, in the form of residual stresses, or a combination of all.
If one of these three components does not exist, this type of corrosion will not occur. Therefore, the solving methods should be based on the elimination of one of these three factors. Corrosive environment modification, the stress in the form of compression, and using proper material are three general proposed methods of prevention.
\n',keywords:"stress corrosion cracking, environments, materials, mechanisms, fracture mechanic",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/63441.pdf",chapterXML:"https://mts.intechopen.com/source/xml/63441.xml",downloadPdfUrl:"/chapter/pdf-download/63441",previewPdfUrl:"/chapter/pdf-preview/63441",totalDownloads:601,totalViews:0,totalCrossrefCites:1,dateSubmitted:"March 21st 2018",dateReviewed:"August 9th 2018",datePrePublished:"September 27th 2019",datePublished:"December 18th 2019",dateFinished:null,readingETA:"0",abstract:"Stress corrosion cracking (SCC) is the formation and growth of crack through materials subjected to tensile stress and a specific corrosive medium. It can lead to unexpected sudden failure of normally ductile metals. Metal-environment combinations susceptible to cracking are specific. This means that all environments do not cause SCC on all of the alloys. Additionally, the environments that cause this kind of cracking have little corrosion effect on the alloy in normal conditions. In certain states, unwanted environmental and metallurgical changes have occurred and provide the metal-environment combination sensitive to SCC. The SCC sites on the metal surfaces may not be visible by visual inspection, while metal parts are being filled with microscopic cracks. These invisible cracks progress rapidly and lead the component and structures to catastrophic failures. In this chapter, the incidence of SCC on important industrial alloys from the chemical, metallurgical, and mechanical point of view is discussed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/63441",risUrl:"/chapter/ris/63441",signatures:"Alireza Khalifeh",book:{id:"7369",title:"Failure Analysis",subtitle:null,fullTitle:"Failure Analysis",slug:"failure-analysis",publishedDate:"December 18th 2019",bookSignature:"Zheng-Ming Huang and Sayed Hemeda",coverURL:"https://cdn.intechopen.com/books/images_new/7369.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"196101",title:"Dr.",name:"Zheng-Ming",middleName:null,surname:"Huang",slug:"zheng-ming-huang",fullName:"Zheng-Ming Huang"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"251415",title:"Ph.D. Student",name:"Alireza",middleName:null,surname:"Khalifeh",fullName:"Alireza Khalifeh",slug:"alireza-khalifeh",email:"areza1006@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Requirements for SCC",level:"1"},{id:"sec_2_2",title:"2.1 Materials",level:"2"},{id:"sec_2_3",title:"2.1.1 Stainless steels",level:"3"},{id:"sec_3_3",title:"2.1.2 Copper and copper alloys",level:"3"},{id:"sec_4_3",title:"2.1.3 Aluminum and aluminum alloys",level:"3"},{id:"sec_5_3",title:"2.1.4 Carbon steels",level:"3"},{id:"sec_6_3",title:"2.1.5 Titanium alloys",level:"3"},{id:"sec_8_2",title:"2.2 Environments",level:"2"},{id:"sec_9_2",title:"2.3 Stress",level:"2"},{id:"sec_11",title:"3. Stress corrosion cracking mechanism",level:"1"},{id:"sec_11_2",title:"3.1 Pre-existing active path mechanism",level:"2"},{id:"sec_12_2",title:"3.2 Strain-generated active path mechanisms",level:"2"},{id:"sec_13_2",title:"3.3 Adsorption-related phenomenon",level:"2"},{id:"sec_15",title:"4. Application of fracture mechanics",level:"1"},{id:"sec_16",title:"5. Prevention",level:"1"},{id:"sec_17",title:"6. Failure case studies",level:"1"},{id:"sec_17_2",title:"6.1 Case 1: stress corrosion cracking of a circulation water heater tube sheet [8]",level:"2"},{id:"sec_17_3",title:"6.1.1 Material and environment",level:"3"},{id:"sec_18_3",title:"6.1.2 Cause",level:"3"},{id:"sec_19_3",title:"6.1.3 Prevention",level:"3"},{id:"sec_21_2",title:"6.2 Case 2: failure of an austenitic stainless steel tubes in a gas-fired steam heater [9]",level:"2"},{id:"sec_21_3",title:"6.2.1 Material and environment",level:"3"},{id:"sec_22_3",title:"6.2.2 Cause",level:"3"},{id:"sec_23_3",title:"6.2.3 Prevention",level:"3"},{id:"sec_25_2",title:"6.3 Case 3: failures of brass condenser tubes [60]",level:"2"},{id:"sec_25_3",title:"6.3.1 Material and environment",level:"3"},{id:"sec_26_3",title:"6.3.2 Cause",level:"3"},{id:"sec_27_3",title:"6.3.3 Prevention",level:"3"},{id:"sec_30",title:"7. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Abedi SS, Abdolmaleki A, Adibi N. 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Effect of microstructures on SCC of steel: Field failure analysis case study and laboratory test result. Engineering Failure Analysis. 2011;18(7):1858-1866'},{id:"B7",body:'Swaminathan J et al. Sensitization induced stress corrosion failure of AISI 347 stainless steel fractionator furnace tubes. Engineering Failure Analysis. 2011;18(8):2211-2221'},{id:"B8",body:'Khalifeh A et al. Stress corrosion cracking of a circulation water heater tubesheet. Engineering Failure Analysis. 2017;78:55-66'},{id:"B9",body:'Parnian N. Failure analysis of austenitic stainless steel tubes in a gas fired steam heater. Materials & Design. 2012;36:788-795'},{id:"B10",body:'Vinoy T et al. Stress corrosion crack growth studies on AISI typ. 316 stainless steel in boiling acidified sodium chloride solution. Journal of Nuclear Materials. 1996;238(2):278-284'},{id:"B11",body:'Li Y et al. Failure analysis of the 304 stainless steel tube in a gas analyzer. Engineering Failure Analysis. 2012;20:35-42'},{id:"B12",body:'Fontana MG. Corrosion Engineering. India: Tata McGraw-Hill Education; 2005'},{id:"B13",body:'Sedriks AJ. Corrosion of Stainless Steel, 2nd ed. USA: Wiley-Interscience; 1996'},{id:"B14",body:'Pal S, Ibrahim R, Raman RS. Studying the effect of sensitization on the threshold stress intensity and crack growth for chloride stress corrosion cracking of austenitic stainless steel using circumferential notch tensile technique. Engineering Fracture Mechanics. 2012;82:158-171'},{id:"B15",body:'Angeliu T et al. Intergranular stress corrosion cracking of unsensitized stainless steels in BWR environments. In: Ninth International Symposium on Environmental Degradation of Materials in Nuclear Power Systems-Water Reactors. Wiley Online Library; 1999'},{id:"B16",body:'Davis JR. Copper and Copper Alloys. USA: ASM International; 2001'},{id:"B17",body:'El-Amoush AS et al. Stress corrosion cracking of the pre-immersed tin brass heat exchanger tube in an ammoniacal solution. Materials & Design (1980–2015). 2014;56:842-847'},{id:"B18",body:'Kannan MB, Shukla P. Stress corrosion cracking (SCC) of copper and copper-based alloys. In: Stress Corrosion Cracking. USA: Elsevier; 2011. pp. 409-426'},{id:"B19",body:'Craig J, Montague W, Pugh E. Factors influencing the path of stress-corrosioncracking in alpha-phase copper alloys exposed to aqueous ammonia environments. ASM Transactions Quarterly. 1968;61(3):468-473'},{id:"B20",body:'Pugh, E., Mechanisms of Stress Corrosion Cracking of Alpha-Brass in Aqueous Ammonia. 1971'},{id:"B21",body:'Sieradzki K et al. The relationship between dealloying and transgranular stress-corrosion cracking of Cu-Zn and Cu-Al alloys. Journal of the Electrochemical Society. 1987;134(7):1635-1639'},{id:"B22",body:'Ohtani N, Dodd R. Mechanisms of transgranular stress corrosion cracking of solid solution alloys. Corrosion. 1965;21(5):161-172'},{id:"B23",body:'Popović M, Romhanji E. Stress corrosion cracking susceptibility of Al-Mg alloy sheet with high Mg content. Journal of Materials Processing Technology. 2002;125:275-280'},{id:"B24",body:'Jones R et al. Role of Mg in the stress corrosion cracking of an Al-Mg alloy. Metallurgical and Materials Transactions A. 2001;32(7):1699-1711'},{id:"B25",body:'Rao AU et al. Stress corrosion cracking behaviour of 7xxx aluminum alloys: A literature review. Transactions of Nonferrous Metals Society of China. 2016;26(6):1447-1471'},{id:"B26",body:'Sridhar N et al. Stress corrosion cracking of carbon steel in ethanol. Corrosion. 2006;62(8):687-702'},{id:"B27",body:'Wang J, Atrens A. SCC initiation for X65 pipeline steel in the “high” pH carbonate/bicarbonate solution. Corrosion Science. 2003;45(10):2199-2217'},{id:"B28",body:'Cheng Y, Steward F. Corrosion of carbon steels in high-temperature water studied by electrochemical techniques. Corrosion Science. 2004;46(10):2405-2420'},{id:"B29",body:'Contreras A et al. Mechanical and environmental effects on stress corrosion cracking of low carbon pipeline steel in a soil solution. Materials & Design. 2012;35:281-289'},{id:"B30",body:'Jones RH. Stress-Corrosion Cracking, Materials Performance and Evaluation. USA: ASM International; 2017'},{id:"B31",body:'Cheng YF. Stress Corrosion Cracking of Pipelines. Vol. 15. USA: John Wiley & Sons; 2013'},{id:"B32",body:'Zardiackas L, Bogan J. Stress corrosion cracking resistance of titanium implant materials. In: 27th Annual Meeting of the Society for Biomaterials in Conjunction with the 33rd International Biomaterials Symposium. 2001'},{id:"B33",body:'Wang J et al. Stress corrosion cracking of NiTi in artificial saliva. Dental Materials. 2007;23(2):133-137'},{id:"B34",body:'Guo X et al. Correlation between passive film-induced stress and stress corrosion cracking of α-Ti in a methanol solution at various potentials. Materials Science and Engineering A. 2003;346(1–2):1-7'},{id:"B35",body:'Trasatti S, Sivieri E. Electrochemical and stress corrosion cracking behaviour of titanium in n-propanol and iso-propanol solutions. Materials Chemistry and Physics. 2004;83(2–3):367-372'},{id:"B36",body:'Pilchak A, Young A, Williams J. Stress corrosion cracking facet crystallography of Ti–8Al–1Mo–1V. Corrosion Science. 2010;52(10):3287-3296'},{id:"B37",body:'Kiefer GC, Harple WW. Stress-corrosion cracking of commercially pure titanium. Metal Progress. 1953;63(2):74-76'},{id:"B38",body:'Blackburn M, Feeney J, Beck T. Stress-corrosion cracking of titanium alloys. In: Advances in Corrosion Science and Technology. USA: Springer; 1973. pp. 67-292'},{id:"B39",body:'Kan W, Pan H. Failure analysis of a stainless steel hydrotreating reactor. Engineering Failure Analysis. 2011;18(1):110-116'},{id:"B40",body:'Shipley RJ, Becker WT, editors. Handbook ASM: Failure Analysis and Prevention. Vol. 11. USA: ASM International; 2002'},{id:"B41",body:'Fairweather N, Platts N, Tice D. Stress-corrosion crack initiation of typ. 304 stainless steel in atmospheric environments containing chloride: Influence of surface condition, relative humidity, temperature and thermal sensitization. In: Corrosion 2008. USA: NACE International; 2008'},{id:"B42",body:'Hayashibara H, Mayuzumi M, Mizutani Y. Effects of temperature and humidity on atmospheric stress corrosion cracking of 304 stainless steel. In: Corrosion 2008. USA: NACE International; 2008'},{id:"B43",body:'Wang Y, Lu Y-B, Pan H-L. Failure analysis of a hydro-processing reactor. Engineering Failure Analysis. 2009;16(1):11-18'},{id:"B44",body:'Raman RS. Role of caustic concentration and electrochemical potentials in caustic cracking of steels. Materials Science and Engineering A. 2006;441(1):342-348'},{id:"B45",body:'Abouswa K, Elshawesh F, Abuargoub A. Stress corrosion cracking (caustic embrittlement) of super heater tubes. Desalination. 2008;222(1):682-688'},{id:"B46",body:'Singh PM, Ige O, Mahmood J. Stress corrosion cracking of typ. 304L stainless steel in sodium sulfide-containing caustic solutions. Corrosion. 2003;59(10):843-850'},{id:"B47",body:'Horowitz HH. Chemical studies of polythionic acid stress-corrosion cracking. Corrosion Science. 1983;23(4):353-362'},{id:"B48",body:'Speidel MO, Hyatt MV. Stress-corrosion cracking of high-strength aluminum alloys. In: Advances in Corrosion Science and Technology. USA: Springer; 1972. pp. 115-335'},{id:"B49",body:'Staehle RW. Fundamental Aspects of Stress Corrosion Cracking: Proceedings of Conference. National Association of Corrosion Engineers; 1969'},{id:"B50",body:'Ghosh S et al. Role of residual stresses induced by industrial fabrication on stress corrosion cracking susceptibility of austenitic stainless steel. Materials & Design. 2011;32(7):3823-3831'},{id:"B51",body:'Turnbull A et al. Sensitivity of stress corrosion cracking of stainless steel to surface machining and grinding procedure. Corrosion Science. 2011;53(10):3398-3415'},{id:"B52",body:'Ahmad Z. Principles of Corrosion Engineering and Corrosion Control. UK: Butterworth-Heinemann; 2006'},{id:"B53",body:'Hoar T, Hines J. In: Robertson WD, editor. Stress Corrosion Cracking and Hydrogen Embrittlement. Vol. 107. New York: John Wiley & Sons; 1956'},{id:"B54",body:'Craig B, Lane R. Environmentally-assisted cracking: Comparing the influence of hydrogen, stress, and corrosion on cracking mechanisms. AMPTIAC Quarterly. 2005;9(1):17-24'},{id:"B55",body:'Champion F. Symposium on Internal Stresses in Metals and Alloys. London: Institute of Metals; 1948. p. 468'},{id:"B56",body:'Murgatroyd J, Sykes R. Mechanism of brittle rupture. Nature. 1945;156(3972):716'},{id:"B57",body:'Dieter GE, Bacon DJ. Mechanical Metallurgy. Vol. 3. New York: McGraw-Hill; 1986'},{id:"B58",body:'Du X et al. Inhibitive effects and mechanism of phosphates on the stress corrosion cracking of brass in ammonia solutions. Corrosion Science. 2012;60:69-75'},{id:"B59",body:'Kannan MB, Raja V. Enhancing stress corrosion cracking resistance in Al-Zn-Mg-Cu-Zr alloy through inhibiting recrystallization. Engineering Fracture Mechanics. 2010;77(2):249-256'},{id:"B60",body:'Bobić B et al. Failures of Brass Condenser Tubes. Integritet I Vek Konstrukcija. 2016;16(1):19-23'},{id:"B61",body:'You S-J et al. Stress corrosion cracking properties of environmentally friendly unleaded brasses containing bismuth in Mattsson’s solution. Materials Science and Engineering A. 2003;345(1–2):207-214'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Alireza Khalifeh",address:"areza1006@gmail.com;, a.khalifeh@shirazu.ac.ir",affiliation:'
Department of Materials Science and Engineering, School of Engineering, Shiraz University, Shiraz, Iran
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BKCI is a part of Web of Science Core Collection (WoSCC) and the world’s leading citation index with multidisciplinary content from the top tier international and regional journals, conference proceedings, and books. The Book Citation Index includes over 104,500 editorially selected books, with 10,000 new books added each year. Containing more than 53.2 million cited references, coverage dates back from 2005 to present. The Book Citation Index is multidisciplinary, covering disciplines across the sciences, social sciences, and arts & humanities.
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Produced by the Web Of Science group, Zoological Record is the world’s oldest continuing database of animal biology. It is considered the world’s leading taxonomic reference, and with coverage back to 1864, has long acted as the world’s unofficial register of animal names. The broad scope of coverage ranges from biodiversity and the environment to taxonomy and veterinary sciences.
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Microsoft Academic is a project exploring how to assist human conducting scientific research by leveraging machine’s cognitive power in memory, computation, sensing, attention, and endurance. Re-launched in 2016, the tool features an entirely new data structure and search engine using semantic search technologies. The Academic Knowledge API offers information retrieval from the underlying database using REST endpoints for advanced research purposes.
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IDEAS is the largest bibliographic database dedicated to Economics and available freely on the Internet. Based on RePEc, it indexes over 3,100,000 items of research, including over 2,900,000 that can be downloaded in full text. RePEc (Research Papers in Economics) is a large volunteer effort to enhance the free dissemination of research in Economics which includes bibliographic metadata from over 2,000 participating archives, including all the major publishers and research outlets. IDEAS is just one of several services that use RePEc data.
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BKCI is a part of Web of Science Core Collection (WoSCC) and the world’s leading citation index with multidisciplinary content from the top tier international and regional journals, conference proceedings, and books. The Book Citation Index includes over 104,500 editorially selected books, with 10,000 new books added each year. Containing more than 53.2 million cited references, coverage dates back from 2005 to present. The Book Citation Index is multidisciplinary, covering disciplines across the sciences, social sciences, and arts & humanities.
Produced by the Web Of Science group, BIOSIS Previews research database provides researchers with the most current sources of life sciences information, including journals, conferences, patents, books, review articles, and more. Researchers can also access multidisciplinary coverage via specialized indexing such as MeSH disease terms, CAS registry numbers, Sequence Databank Numbers and Major Concepts.
Produced by the Web Of Science group, Zoological Record is the world’s oldest continuing database of animal biology. It is considered the world’s leading taxonomic reference, and with coverage back to 1864, has long acted as the world’s unofficial register of animal names. The broad scope of coverage ranges from biodiversity and the environment to taxonomy and veterinary sciences.
Provides a simple way to search broadly for scholarly literature. Includes peer-reviewed papers, theses, books, abstracts and articles, from academic publishers, professsional societies, preprint repositories, universities and other scholarly organizations. Google Scholar sorts articles by weighing the full text of each article, the author, the publication in which the article appears, and how often the article has been cited in other scholarly literature, so that the most relevant results are returned on the first page.
Microsoft Academic is a project exploring how to assist human conducting scientific research by leveraging machine’s cognitive power in memory, computation, sensing, attention, and endurance. Re-launched in 2016, the tool features an entirely new data structure and search engine using semantic search technologies. The Academic Knowledge API offers information retrieval from the underlying database using REST endpoints for advanced research purposes.
The national library of the United Kingdom includes 150 million manuscripts, maps, newspapers, magazines, prints and drawings, music scores, and patents. Online catalogues, information and exhibitions can be found on its website. The library operates the world's largest document delivery service, providing millions of items a year to national and international customers.
The digital NSK portal is the central gathering place for the digital collections of the National and University Library (NSK) in Croatia. It was established in 2016 to provide access to the Library’s digital and digitized material collections regardless of storage location. The digital NSK portal enables a unified search of digitized material from the NSK Special Collections - books, visual material, maps and music material. From the end of 2019, all thematic portals are available independently: Digital Books, Digitized Manuscripts, Digitized Visual Materials, Digital Music Materials and Digitized Cartographic Materials (established in 2017). Currently available only in Croatian.
The official DOI (digital object identifier) link registration agency for scholarly and professional publications. Crossref operates a cross-publisher citation linking system that allows a researcher to click on a reference citation on one publisher’s platform and link directly to the cited content on another publisher’s platform, subject to the target publisher’s access control practices. This citation-linking network covers millions of articles and other content items from several hundred scholarly and professional publishers.
Dimensions is a next-generation linked research information system that makes it easier to find and access the most relevant information, analyze the academic and broader outcomes of research, and gather insights to inform future strategy. Dimensions delivers an array of search and discovery, analytical, and research management tools, all in a single platform. Developed in collaboration with over 100 leading research organizations around the world, it brings together over 128 million publications, grants, policy, data and metrics for the first time, enabling users to explore over 4 billion connections between them.
The primary aim of DOAB (Directory of Open Access Books) is to increase discoverability of Open Access books. Metadata will be harvestable in order to maximize dissemination, visibility and impact. Aggregators can integrate the records in their commercial services and libraries can integrate the directory into their online catalogues, helping scholars and students to discover the books.
OAPEN is dedicated to open access, peer-reviewed books. OAPEN operates two platforms, the OAPEN Library (www.oapen.org), a central repository for hosting and disseminating OA books, and the Directory of Open Access Books (DOAB, www.doabooks.org), a discovery service for OA books.
OpenAIRE aims at promoting and implementing the directives of the European Commission (EC) and the European Research Council on the promotion and funding of science and research. OpenAIRE supports the Open Access Mandate and the Open Research Data Pilot developed as part of the Horizon 2020 projects.
An integrated information service combining reference databases, subscription management, online journals, books and linking services. Widely used by libraries, schools, government institutions, medical institutions, corporations and others.
SFX® link resolver gives patrons and librarians a wealth of features that optimize management of and access to resources. It provides patrons with a direct route to electronic full-text records through OpenURL linking, delivers alternative links for further resource discovery, access to journals, and more. Released in 2001 as the first OpenURL resolver, SFX is continuously enhanced to support the newest industry developments and meet the evolving needs of customers. The records include a mix of scholarly material – primarily articles and e-books – but also conference proceedings, newspaper articles, and more.
A non-profit, membership, computer library service and research organization dedicated to the public purposes of furthering access to the world's information and reducing information costs. More than 41,555 libraries in 112 countries and territories around the world use OCLC services to locate, acquire, catalogue, lend and preserve library materials.
The world’s largest collection of open access research papers. CORE's mission is to aggregate all open access research outputs from repositories and journals worldwide and make them available to the public. In this way CORE facilitates free unrestricted access to research for all.
Perlego is a digital online library focusing on the delivery of academic, professional and non-fiction eBooks. It is a subscription-based service that offers users unlimited access to these texts for the duration of their subscription, however IntechOpen content integrated on the platform will always be available for free. They have been billed as “the Spotify for Textbooks” by the Evening Standard. Perlego is based in London but is available to users worldwide.
MyScienceWork provides a suite of data-driven solutions for research institutions, scientific publishers and private-sector R&D companies. MyScienceWork's comprehensive database includes more than 90 million scientific publications and 12 million patents.
CNKI (China National Knowledge Infrastructure) is a key national information construction project under the lead of Tsinghua University, and supported by PRC Ministry of Education, PRC Ministry of Science, Propaganda Department of the Communist Party of China and PRC General Administration of Press and Publication. CNKI has built a comprehensive China Integrated Knowledge Resources System, including journals, doctoral dissertations, masters' theses, proceedings, newspapers, yearbooks, statistical yearbooks, ebooks, patents, standards and so on. CNKI keeps integrating new contents and developing new products in 2 aspects: full-text academic resources, software on digitization and knowledge management. Began with academic journals, CNKI has become the largest and mostly-used academic online library in China.
As one of the largest digital content platform in China,independently developed by CNPIEC, CNPeReading positions herself as “One Platform,Vast Content, Global Services”. Through their new cooperation model and service philosophy, CNPeReading provides integrated promotion and marketing solutionsfor upstream publishers, one-stop, triune, recommendation, online reading and management servicesfor downstream institutions & libraries.
ERIC (Education Resources Information Center), sponsored by the Institute of Education Sciences (IES) of the U.S. Department of Education, provides access to education literature to support the use of educational research and information to improve practice in learning, teaching, educational decision-making, and research. The ERIC website is available to the public for searching more than one million citations going back to 1966.
The ACM Digital Library is a research, discovery and networking platform containing: The Full-Text Collection of all ACM publications, including journals, conference proceedings, technical magazines, newsletters and books. A collection of curated and hosted full-text publications from select publishers.
BASE (Bielefeld Academic Search Engine) is one of the world's most voluminous search sengines especially for academic web resources, e.g. journal articles, preprints, digital collections, images / videos or research data. BASE facilitates effective and targeted searches and retrieves high quality, academically relevant results. Other than search engines like Google or Bing BASE searches the deep web as well. The sources which are included in BASE are intellectually selected (by people from the BASE team) and reviewed. That's why data garbage and spam do not occur.
Zentralblatt MATH (zbMATH) is the world’s most comprehensive and longest-running abstracting and reviewing service in pure and applied mathematics. It is edited by the European Mathematical Society (EMS), the Heidelberg Academy of Sciences and Humanities and FIZ Karlsruhe. zbMATH provides easy access to bibliographic data, reviews and abstracts from all areas of pure mathematics as well as applications, in particular to natural sciences, computer science, economics and engineering. It also covers history and philosophy of mathematics and university education. All entries are classified according to the Mathematics Subject Classification Scheme (MSC 2020) and are equipped with keywords in order to characterize their particular content.
IDEAS is the largest bibliographic database dedicated to Economics and available freely on the Internet. Based on RePEc, it indexes over 3,100,000 items of research, including over 2,900,000 that can be downloaded in full text. RePEc (Research Papers in Economics) is a large volunteer effort to enhance the free dissemination of research in Economics which includes bibliographic metadata from over 2,000 participating archives, including all the major publishers and research outlets. IDEAS is just one of several services that use RePEc data.
As the authoritative source for chemical names, structures and CAS Registry Numbers®, the CAS substance collection, CAS REGISTRY®, serves as a universal standard for chemists worldwide. Covering advances in chemistry and related sciences over the last 150 years, the CAS content collection empowers researchers, business leaders, and information professionals around the world with immediate access to the reliable information they need to fuel innovation.
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He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. 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His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. 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