1. Introduction
1.1. Rationale for comparison of MCM and RecQ helicase families
DNA helicases are currently organized into superfamilies based on their sequence structures and 3-D conformations. Within each superfamily, there are members that have further evolved for specialized functions [1]. There is conservation of RecQ proteins from bacteria to humans. Whereas bacteria have one RecQ helicase, humans have evolved at least five different proteins [2]. The RecQ members belong to the helicase Superfamily II, and as such have the characteristic Rec fold [1]. In this chapter, we will focus on RecQ family members WRN, BLM and RECQL4 (RecQ protein-like 4), which is also referred to in the literature as RECQ4. Eukaryotic and archaeal MCMs belong to the helicase Superfamily VI, and have the AAA+ (ATPases associated with diverse cellular activities) fold [1, 3, 4, 5]. Both Rec and AAA+ folds are based on the ancestral ASCE (additional strand conserved E) fold or an alpha-beta-alpha domain necessary for nucleoside triphosphate binding and catalysis [1, 6, 7]. A rationale for comparison of the RecQ and MCM family members relates to the importance of their activities for genomic integrity. The WRN and BLM proteins as well as other members of the RecQ family are characterized by this feature [8]. Both WRN and BLM are involved in DNA repair and a role for WRN in telomere homeostasis in humans is well established [2, 9]. MCM2-7 proteins, along with cofactors, are thought to function as the eukaryotic replicative helicase [10]. MCM8 [11, 12] and MCM9 [13, 14] are more recently discovered and their roles are less well defined. Although data point to a role for MCM8 in DNA replication, that role may be specialized in higher organisms. In human cells, MCM10 is recruited to chromosomal domains before they replicate and studies in yeast suggest a role in DNA replication, but not as a helicase [15-18]. Members of each family are essential for chromosome homeostasis. When replication forks stall, there may be involvement of members of each family. These proteins have interlocking functions since, for example, a stalled replication fork with attendant MCM proteins can lead to a DNA double-strand break (DSB), which requires RecQ proteins for repair [19].
2. RecQ and MCM family structures
Breaks in double-strand DNA can occur during DNA replication, at specific loci (e.g., at telomeres) and during meiosis. RecQ helicases are implicated in DNA repair based on their involvement in such processes as DNA end resection, branch migration, D-loop processing, Holliday Junction (HJ) and double Holliday junction (dHJ) resolution [2]. RecQ proteins function at multiple steps, both early and late, during repair of DSB [19]. RecQ helicases travel in a 3’ to 5’ direction on ssDNA [20]. The RecQ proteins have an ancient lineage based on an ancestral ASCE fold (αβα domain) of distant relation to P-loop NTPase folds. RecQ structural domains include a conserved core helicase domain for binding and hydrolysis of nucleoside triphosphate that is equivalent to the Walker A and Walker B boxes seen in MCM proteins [21]. They have a helicase and RNAase D C-terminal (HRDC) domain thought to mediate structure-specific nucleic acid binding, double HJ dissolution and protein-protein interactions. They also have a RecQ C-terminal (RQC) domain thought to mediate interactions with other proteins, structure-specific nucleic acid binding and metal cofactor binding [22]. Acidic regions present in many RecQ proteins aid in protein-protein interactions. There are also nuclear localization signals in some RecQ proteins (e.g.,
RECQL4 has been reported to have ssDNA binding and DNA strand-annealing activities. In this single study, RECQL4 did not display substrate unwinding or resolution of substrates resembling replication or recombination intermediates [23]. Recognizable HRDC and RQC domains that are important in BLM activity are missing in RECQL4 [22, 24]. As observed, the ssDNA annealing activity would allow RECQL4 to function during synthesis-dependent strand annealing (SDSA) along with another helicase. RECQL4 could help direct pathway choice during HR in DSB repair through aiding ssDNA annealing activity in non-homologous end joining (NHEJ) [19]. Thus, RECQL4 is similar to other RecQ helicases in its core helicase domain, but its function as a helicase is unclear [23, 25, 26].
AAA+ proteins, including MCMs, have a core molecular motor. Like the RecQ proteins, the AAA+ fold is also based on the ancestral ASCE fold. Acquisition of a catalytic glutamate (Fig. 1) to initiate efficient hydrolysis of ATP marked the emergence of the ASCE division from the ancestral P-loop fold [7]. For further discussion of the glutamate “switch” in AAA+ proteins, see reference [27]. Mechanisms of action are diverse, although members are typically oligomeric ring assemblies with inter-subunit communication. The central AAA+ motor has been adapted in evolution through structural changes to the core module and through domains added either N- or C-terminal to the AAA+ core. Activities are facilitated by recognition of protein partners functioning in these diverse events. Thus, AAA+ proteins display a variety of macromolecular remodelling events that are energy-driven by nucleotide hydrolysis thought to be occurring throughout what is typically a hexameric complex assembly [28, 29]. The conserved Walker A and Walker B motifs within the central module mediate ATP-binding and hydrolysis [7, 30-32]. MCM proteins have two active site motifs, the P-loop domain and the lid. Motifs in the P-loop include Walker A, Walker B and Sensor 1. The lid domain contains the arginine finger and Sensor 2. A catalytic site is created by a dimer interface that employs a
3. RecQ and MCM helicases: association with disease and aging
3.1. BLM and Bloom syndrome, WRN and Werner syndrome, RECQL4 and Rothmund-Thomson syndrome
As a group, mutations in the RecQ helicases lead to adult segmental progeria with abnormalities in development, predisposition to cancer and acceleration of aging processes. Three of the RecQ family members are associated with rare autosomal recessive diseases [19]. These disorders Werner syndrome (WS) [35], Bloom syndrome (BS) [36] and Rothmund-Thomson syndrome (RTS) [37, 38] are caused by mutations in the genes coding for WRN, BLM and RECQL4, respectively. RTS is a heterogeneous disorder with about 60% of cases resulting from mutations in the
BS manifests in pleiotropic phenotypes such as growth retardation leading to proportional dwarfism, erythema with light sensitivity, skin lesions with hypo- and hyperpigmentation, immunodeficiency, susceptibility to type II diabetes, male infertility, female sub-fertility, reports of mental retardation, cancer predisposition (all types but at an earlier age of diagnosis than in the normal population).
WS leads to short stature and early onset age-related diseases, including greying hair, alopecia, bilateral cataracts, osteoporosis, arteriosclerosis, atherosclerosis, skin atrophy, hypogonadism, type II diabetes mellitus and susceptibility to tumors, especially those of mesenchymal origin (sarcomas).
RTS manifests as early growth deficiency, congenital bone defects, poikiloderma, cataracts, greying hair, alopecia, hypogonadism, and some increased susceptibility to cancer, especially osteogenic sarcomas.
3.2. MCMs and genomic stability
The MCM proteins 2-7 are necessary for DNA replication in yeast [45, 46], and this basic life function extends in evolution to a single MCM protein in archaea [47-49]. MCM2-7 are also essential for replication in
Due to their essential roles, it is not surprising that there are few diseases directly ascribed to defects in MCMs 2-7. This does, however, bring up an unresolved MCM enigma: there are more MCM proteins than are required to form initiation complexes at cellular origins active within a given round of DNA replication [71]. In addition, MCM proteins in human cells remain at peak levels in G2 phase of the cell cycle, after DNA replication is complete [59, 72, 73] This high copy number could be an aspect of securing sufficient protein quantities for basic function. A role for MCM proteins in transcription has also been proposed, and this remains to be defined [74]; for further discussion see reference [46]. Redundancy of functions among MCM members is also a factor to be considered. Intriguingly, knockdown of MCM8 [75], not even present in yeast [12], retards S-phase approximately 25% in human cells in culture [75], suggesting a specialized function in higher eukaryotes critical for basic replication. It has been suggested that the excess MCMs license dormant origins, which are used under conditions of stress upon normally functional origins [71]. An overview provides a discussion of recent work connecting dormant origins of replication and tumor suppression based on the role of dormant origins during fork restart after repair of DNA damage [76].
Mutations in MCM family members have been studied in yeast and mouse models, and they confirm an essential role for MCM2-7 in DNA replication [34, 45, 77, 78]. A human MCM4 mutation (destabilizing the MCM2-7 complex) was recently reported concurrently by two groups who studied consanguineous families, and the resulting phenotype was found to be associated with immune deficiency (NK cells), adrenal insufficiency and short stature [79, 80]. Patient fibroblasts showed chromosome fragility [79]. The susceptibility of these patients to cancer is not currently known [80]. An
3.2.1. A structural domain deleted from MCM8 and present in WRN and BLM
A brief discussion of MCM8 is included in this section because it contains a motif that may be structurally similar to one found in BLM and WRN and is linked to neoplasia. Human MCM8 has a splice variant that results in a 16 amino acid (aa) deletion in a location between the Zn finger of MCM8 and its Walker A box [12], Fig. 2. Thus far this deletion has been detected by various different groups only in cases of choriocarcinoma. MCM8 with this same sequence deleted (Fig. 2) has, however, been detected in several higher eukaryotes other than humans, suggesting that the variant does have, or perhaps lacks, a function. That function is as yet unknown, but clues to it may be gleaned from a comparison of the MCM8 deletion with sequences from WRN and BLM. These RecQ proteins have a counterpart 16 aa domain with partial sequence homology and notable structural homology, as denoted in Fig. 2. This sequence in the RecQ proteins is located in a different orientation to that of MCM8 with regard to the helicase Walker A and B boxes (Fig. 2). In each case the first 8 aa of this sequence are highly charged and, in WRN, BLM and MCM8, contain a polar S. The 9th aa in this deletion is a conserved C. The remaining 7 aa contain a preponderance of aromatic and hydrophobic residues. This configuration of charged and aromatic residues is characteristic of known single-stranded nucleic acid binding proteins [87]. Among MCMs, this 16 aa domain is identifiable in the single MCM of
4. Supportive roles for WRN, BLM helicases and RECQL4 during replication elongation
During normal metabolism, such as in mitochondrial respiration, endogenous reactive oxygen species (ROS) are produced that lead to oxidative DNA modifications. In addition to endogenous mutagens, there are also environmental mutagens that damage the DNA [90]. Furthermore, during replication and transcription, duplex DNA is transiently opened, and there is an opportunity for non-B DNA structures to form in the genomic DNA [40]. RecQ helicases act on recombination intermediates, on preferred substrates including those resembling G-quadruplex DNA [91, 92], D-loops [93], HJ [94] and double HJ [95]. RecQ helicases may play a regulatory role in both pro- and anti-HR events. They function at the interface of HR with the stressed replication fork and may affect repair pathway choice. There is little evidence for a specific clear cut role, but for a discussion of proposed mechanistic models of RecQ protein function, see the references [19, 20].
4.1. BLM and RECQL4
In BS cells, there are S-phase defects in DNA replication involving abnormal replication intermediates, and replication elongation is slower [96-98]. These cells don’t recover well from induced fork stalling and accumulate DSB [99, 100]. In human cells, RECQL4 interacts with the MCM2-7 complex, Cdc45 and GINS. The interaction is facilitated by MCM10 [25]. BLM and RECQL4 are at their highest levels during S phase. At stalled replication forks, BLM physically associates with Rad51 and p53, and BLM and p53 function synergistically in HR [101]. BLM colocalizes in foci with PCNA and with the BASC (BRCA1-associated genome surveillance complex) [102]. BLM is phosphorylated by ATR [103]. When replication forks are stalled by use of hydroxyurea (HU), BLM colocalizes with Chk1 and p53BP1 foci. Chk1 is required for BLM and 53BP1 foci formation. Thus Chk1 may recruit BLM to stalled forks [104]. This implicates RecQ proteins as DNA damage checkpoint mediators in response to stalled forks.
Aberrant replication intermediates arise in cells lacking WRN and BLM [97, 125]. Such unresolved replication or recombination structures lead to incomplete chromosome segregation. BLM, topoisomerase 3 alpha (Topo3α) and BLAP75/RMI1 (for BLM-associated polypeptide/RecQ-mediated genome instability) or a BLM-Topo3α-BLAP75/RMI1 complex localizes to resulting anaphase bridges [126]. A helicase known as PICH arrives first, followed by the resolution activity of BLM [127]. As helicases unwind duplex DNA, torsional stress produced in the DNA may require relief through topoisomerase activity, and such activity finally decatenates interlocked DNA molecules [128, 129].
4.2. WRN
Over 50 distinct
WRN and BLM catalytic activities are comparable except for 3’ to 5’ exonuclease activity of WRN [151-153], which BLM lacks. On dsDNA and on RNA-DNA hybrids, the WRN exonuclease activity degrades a 3’ recessed end. This activity can remove only one mismatched NT at the end of the recessed 3’ DNA and can initiate exonuclease activity from a gap or nick [154, 155]. The exonuclease activity of WRN can degrade abnormal DNA structures suggesting that WRN helicase and exonuclease activities are involved in resolution of aberrant DNA structures at stalled forks [156]. Human WRN interacts with proteins involved in DNA replication. WRN coimmunoprecipitates with PCNA and topoisomerase 1 [157]. WRN functionally and physically interacts with RPA [117], and it functionally interacts with DNA polymerase delta [152]. WS cells accumulate recombination intermediates that impede cell growth [158]. In cells treated with HU, WRN colocalizes with RPA foci and is thought to dissociate recombination intermediates at the stalled forks [94, 147]. WRN stimulates polymerase delta activity in the absence of its processivity factor PCNA. This suggests a role for WRN in recruiting polymerase delta for replication restart at blocked or collapsed forks [152]. RPA can stimulate the processivity of WRN. The stimulation of WRN by RPA is due to protein-protein interactions as opposed to enhanced ATPase activity [117, 118].
5. Unification of BLM, WRN, RECQL4 and MCM2-7 activities in DNA replication and recombination/repair
5.1. BLM: Role in DNA damage response with a complex role in inhibiting or promoting HR
BLM is found mostly in fine granules throughout the nucleoplasm at highest levels during S and G2 phases of the cell cycle. Its focal localization is in PML nuclear bodies (PML-NB). The name PML derives from the promyelocytic leukemia protein, PML [159-162]. This protein forms the structural groundwork of the PML bodies, which store various nuclear proteins [163]. These PML-NB store repair proteins (e.g., Topo3α, MRN and p53) and may be involved in sensing DNA damage [163]. By regulating the availability of repair proteins, response can be directed to DNA damage sites. Trafficking of proteins to the PML-NB is regulated by sumoylation [164]. The sumoylation pathway involves E1, E2 and E3 enzymes, which regulate respectively, SUMO activation, SUMO conjugation and targeting of specific substrates for sumoylation through ligation [165]. BLM contains a motif for SUMO binding that would facilitate its integration into this repair protein storage network [166]. In addition, BLM is SUMO-1 and SUMO-2 modified [167]. When mutants are prepared in which the SUMO-binding sequences are deleted, BLM cannot localize to PML-NB [168]. When mutants are prepared that do not allow BLM localization to PML-NB, there is about a two-fold increase in sister chromatid exchange. These findings indicate that there is a need for BLM-SUMO interaction in order for BLM to localize to PML-NB, and that BLM activity, such as its accumulation at stalled replication forks, may be regulated by this specific localization [168].
At sites of DSB, repair foci form. A central player, H2AX, is phosphorylated when DSBs are induced, and this phosphorylation involves ATM, ATR and DNA-PK. Over one million bp are then marked by phosphorylated H2AX (γH2AX) on each side of the break [112, 168-171]. γH2AX recruits additional repair proteins to the damage site [172]. In studies where normal S-phase cells are treated with DNA damaging agents (HU, UV and cross-linking agents), BLM responds by leaving the PML-NBs to relocate to repair foci and colocalize with the marker γH2AX [101, 173]. BLM interacts physically and functionally with γH2AX as well as with ATM and ATR [103, 173-175]. In damage that is S-phase specific, BLM associates with the complex ATR/CHK1/53BP1, which gathers at repair foci as an early response to the damage. Based on kinetic studies, BLM may facilitate BRCA1 and MRN complex localization at repair foci in S phase [173], which may involve BLM regulation of p53 in these foci [101]. This early function of BLM at repair foci may allow for BML to influence the choice of repair pathways and facilitate a BLM function in anti-recombination at stalled forks that perhaps involves SUMO regulation [19].
As discussed in the previous section, BLM interacts with the recombinase, Rad51. Rad51 catalyzes the pairing of a ssDNA tail and a homologous stretch of dsDNA to promote strand exchange early in the HR pathway [111]. Following ionizing radiation, Rad51 foci contained BLM [159]. Rad51 functions in HR, and localizes to ssDNA when DSB are induced [176]. BML can displace the recombinase from the ssDNA filament [112], which can be viewed as an anti-recombinagenic function [19]. In Rad51-associated D-loops, BLM can interact with Rad51 and unwind DNA in front of the polymerase [177]. This could favor SDSA leading to pro-recombinagenic function [19, 177]. BLM, however, also functions in resolution of G-quadruplex DNA structure and has higher binding affinity for it compared to HJ. BLM helicase activity is required for resolution of this structure [92]. Whereas the BLM/Rad51 interaction would represent an early event in a DNA damage/repair process, the formation of HJ, on the other hand, is a late event in HR. As discussed in section 5.1, the BLM-Topo3α-BLAP75/RMI1 complex functions to “dissolve” dHJ by convergent fork migration to generate non-cross-over products [178]. This is facilitated by Topo3α relief of superhelicity and by its ability to cleave and rejoin one strand of a DNA duplex. In the absence of BLM, Topo3α activity would involve break and rejoining activities instead of dissolution, which could lead to crossover events and an increase in sister chromatid exchange in BS cells [19]. BLM that is mutated to be unable to interact with Topo3α can only partially rescue the frequency of sister chromatid exchange [168]. Thus, together in a complex, BLM and Topo3α achieve dissolution of a recombinogenic intermediate. BLM has been proposed to regulate ploidy based on a role along with other members of this complex in resolution of anaphase bridges [126]. BLM has been found in complexes with mismatch repair protein MLH1 [179, 180]. It has been found to be present in large complexes containing not only BLM-Topo3a-BLAF75, but also additional factors. These additional factors could include several BLAF factors, proteins from the FA (Fanconi anemia) pathway, RPA, and mismatch repair protein MLH1. [181, 182]. The interactive role of these pathway components remains to be determined.
5.2. WRN: Helicase and exonuclease activities in concert
When WRN biochemical activities were compared using nonhydrolyzable ATPγS to inhibit only WRN helicase activity or aa substitutions to eliminate only the WRN exonuclease activity, the exonuclease activity was shown to function in degradation of the leading strand on replication fork-type substrates and in degradation of the annealed telomere overhangs on substrates resembling D-loop structures. WRN binding proteins were inhibitory [149, 183]. In addition, WRN was found to degrade ssDNA substrates longer than 40 nt with dependence upon the helicase activity [183]. WRN activities were also explored using WS fibroblasts. In WS cells, WRN and the enzyme telomerase are able to reverse the phenotype of excess chromosome fusion. In these cells, the anaphase bridges were missing telomere DNA. Dominant negative telomerase was not able to rescue the phenotype indicating that a stable telomere length was needed for rescue [184]. Telomeres are stabilized by a complex of proteins that bind DNA, known as the shelterin complex [185]. This complex consists of TRF1, TRF2 (double-strand DNA binding proteins), and POT1 (single-strand DNA binding protein) as well as adaptor proteins. The coordinate action of these proteins in the presence of telomerase is needed to regulate telomere length. Without telomerase, telomeres shorten in length each cell division [185]. In S phase, WRN colocalizes with TRF2 [145, 186]. TRF1 and TRF2 limit WRN exonuclease activity on synthetic telomere D-loops [149]. WRN helicase is stimulated by single-stranded DNA binding proteins, RPA or POT1. These proteins modulate WRN exonuclease degradation of the 3’ overhang [149, 187]. The hypothesis is that WRN could unwind D-loops to facilitate leading strand synthesis through telomeric DNA, and there is also the possibility that WRN prevents interchromosomal interactions between telomeres [19].
5.2.1. WRN activities in response to G-quadruplex structures in the lagging strand
At the telomere, the G-rich strand is duplicated by lagging-strand synthesis. It may assume a G-quadruplex structure, which would interrupt the replication fork. Experimentally, when inhibiting WRN by use of overexpression of a dominant-negative WRN, the helicase deficiency leads to loss almost entirely affecting the sister telomere on the lagging strand [145]. WRN interaction with FEN-1 (the flap endonuclease involved in the processing of Okazaki fragments, [188]) could assist in the maturation of these fragments [105, 189]. Data suggest that WRN may function in concert with lagging strand synthesis perhaps in unwinding complex structure at the telomere. WRN interacts physically with DNA polymerase delta to stimulate its activity [190]. WRN can prevent stalling of polymerases delta at telomere sequence
5.2.2. WRN and Ku in suppression of aberrant recombination at telomeres
Proteins involved in the NHEJ path for repair of DSBs that are found at telomeres include Ku heterodimer, DNA-PK, MRN complex and ATM [193]. Through interaction with NBS1, WRN colocalizes with two of these components, Ku and the MRN complex [194]. Under unstable conditions, Ku can suppress sister chromatid exchange at telomeres [195]. Mouse knockout studies show that WRN normally suppresses aberrant recombination at telomeres [196].
5.2.3. WRN activities in base excision repair and interstrand cross link repair by HR
WS cells show increased sensitivity to alkylating agents and to agents that increase ROS. Human fibroblasts in which WRN has been knocked down respond to oxidative stress with an increase in DNA damage [197]. These observations support a role for WRN in repair of such damage [198]. DNA damage resulting from oxidation, alkylation, methylation and deamination is repaired by the base excision repair (BER) pathway. WRN interacts with proteins in this pathway. In addition, WRN helicase activity stimulates and is stimulated by polymerase beta activity [199]. There is evidence that WRN activity in BER is regulated by PARP-1, but the reader is referred to references [200, 201]. BRCA1 and BRCA2 play an important role in DSB repair in the HR subpathway [202, 203]. HR is a pathway for repairing interstrand crosslinks (ICL). Cells deficient in either WRN or BRCA1 are hypersensitive to induction of ICLs [204, 205]. A physical interaction of WRN with BRCA1 enhances the activities of WRN [206]. In addition, data from WRN and/or BRCA1 knockdown studies indicate that BRCA1 may act cooperatively with WRN in HR during ICL repair [206].
5.3. RECQL4
Data from
5.4. MCM2-7
Replication fork stalling, can lead to DSB and chromosomal rearrangements. An S phase checkpoint is triggered by these events and there is a block to elongation. When this occurs, the proteins Mrc1, Tof1, and Csm3 (M/T/C complex) interact with the MCM2-7 complex to stabilize the replication fork. When the M/T/C complex is missing, the replisome continues, but synthesis stops. This may be partially due to loss of DNA polymerase epsilon from the fork [217-219]. Studies in yeast provide insight into these activities. The M/T/C complex associates with MCM2-7 [218, 220-222] and also with polymerase epsilon [221, 223]. These physical interactions permit communication between polymerase epsilon and the MCM complex [223]. The M/T/C complex may be part of the normal replication fork protein entourage [218, 220, 221, 224]. Mrc1 and Cdc45 coimmunoprecipitate, indicating an interaction of Mrc1 with the The Replication Progression Complex core, which includes Cdc45, the MCMs and GINS [223]. In each cell cycle Mrc loads onto replication origins along with the polymerases. This occurs after the Replication Progression Complex forms. Mrc migrates with the replication forks. [218, 219, 224-226]. Tof1, like Mrc, also coimmunoprecipitates with Cdc45 [227]. The exact mechanism of action of the M/T/C complex is not known. In a yeast study, the Tof1 homologue could switch regulation between pro- and anti-recombination activities in a site-specific manner [228]. Data indicate that a Mrc1 and MCM6-C terminal interaction senses alkylated DNA damage [221]. The other two subunits Tof1 and Csm3, may function to sense other types of damage. Although the helicase domains of MCM2-7 are conserved, the N and C terminals are divergent. Other negative regulators could differentially bind to these regions to regulate powering of elongation by the MCM2-7 helicase during times of stress [10]. A future question relates to the extent to which leading or lagging strand polymerase arrest is associated with formation of ssDNA, fork regression and formation of abnormal DNA structures [66]. These data indicate a functional connection between the MCM proteins, which act at stalled forks, and the RecQ proteins, which facilitate repair of the resulting damage.
6. Summary
BLM, WRN and RECQL4 act during events that stress the advancing replication fork providing relief through DNA damage repair and through resolution of aberrant replication/ recombination intermediates, including those present at the telomere. At checkpoint, the replication proteins at a stalled fork are held stable through communication that occurs due to proteins that bind and signal to both the MCM complex and polymerase(s). This would allow repair proteins such as WRN and BLM helicases and RECQL4 to resolve the stress and thus aid in fork restart. Advancing our knowledge of the RecQ and MCM family activities and the mechanisms and signalling behind these activities will increase our understanding of cancer and aging and perhaps enlighten us regarding how to accommodate these challenges to human health.
Acknowledgments
This. work was supported by NIH funding to EMJ and resources derived from grant funding from Virginia’s Commonwealth Health Research Board to DCD.
References
- 1.
Berger JM. SnapShot: nucleic acid helicases and translocases. Cell. 2008 Sep 5;134(5):888- e1. 18775318 - 2.
Bernstein KA, Gangloff S, Rothstein R. The RecQ DNA helicases in DNA repair. Annu Rev Genet. 2010;44:393-417. 21047263 - 3.
Kelman Z, Hurwitz J. Structural lessons in DNA replication from the third domain of life. Nat Struct Biol. 2003 Mar;10(3):148-50. 12605215 - 4.
Erzberger JP, Berger JM. Evolutionary relationships and structural mechanisms of AAA+ proteins. Annu Rev Biophys Biomol Struct. 2006;35:93-114. 16689629 - 5.
Koonin EV. A common set of conserved motifs in a vast variety of putative nucleic acid-dependent ATPases including MCM proteins involved in the initiation of eukaryotic DNA replication. Nucleic Acids Res. 1993 Jun 11;21(11):2541-7. 8332451 - 6.
Iyer LM, Leipe DD, Koonin EV, Aravind L. Evolutionary history and higher order classification of AAA+ ATPases. J Struct Biol. 2004 Apr-May;146(1-2):11-31. 15037234 - 7.
Leipe DD, Koonin EV, Aravind L. Evolution and classification of P-loop kinases and related proteins. J Mol Biol. 2003 Oct 31;333(4):781-815. 14568537 - 8.
Mohaghegh P, Hickson ID. DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum Mol Genet. 2001 Apr;10(7):741-6. 11257107 - 9.
Brosh RM, Jr., Bohr VA. Human premature aging, DNA repair and RecQ helicases. Nucleic Acids Res. 2007;35(22):7527-44. 18006573 - 10.
Bochman ML, Schwacha A. The Mcm complex: unwinding the mechanism of a replicative helicase. Microbiol Mol Biol Rev. 2009 Dec;73(4):652-83. 19946136 - 11.
Gozuacik D, Chami M, Lagorce D, Faivre J, Murakami Y, Poch O, Biermann E, Knippers R, Brechot C, Paterlini-Brechot P. Identification and functional characterization of a new member of the human Mcm protein family: hMcm8. Nucleic Acids Res. 2003 Jan 15;31(2):570-9. 12527764 - 12.
Johnson EM, Kinoshita Y, Daniel DC. A new member of the MCM protein family encoded by the human MCM8 gene, located contrapodal to GCD10 at chromosome band 20p12.3-13. Nucleic Acids Res. 2003 Jun 1;31(11):2915-25. 12771218 - 13.
Lutzmann M, Maiorano D, Mechali M. Identification of full genes and proteins of MCM9, a novel, vertebrate-specific member of the MCM2-8 protein family. Gene. 2005 Dec 5;362:51-6. 16226853 - 14.
Yoshida K. Identification of a novel cell-cycle-induced MCM family protein MCM9. Biochem Biophys Res Commun. 2005 Jun 3;331(2):669-74. 15850810 - 15.
Fien K, Cho YS, Lee JK, Raychaudhuri S, Tappin I, Hurwitz J. Primer utilization by DNA polymerase alpha-primase is influenced by its interaction with Mcm10p. J Biol Chem. 2004 Apr 16;279(16):16144-53. 14766746 - 16.
Ricke RM, Bielinsky AK. Mcm10 regulates the stability and chromatin association of DNA polymerase-alpha. Mol Cell. 2004 Oct 22;16(2):173-85. 15494305 - 17.
Sawyer SL, Cheng IH, Chai W, Tye BK. Mcm10 and Cdc45 cooperate in origin activation in Saccharomyces cerevisiae. J Mol Biol. 2004 Jul 2;340(2):195-202. 15201046 - 18.
Yang X, Gregan J, Lindner K, Young H, Kearsey SE. Nuclear distribution and chromatin association of DNA polymerase alpha-primase is affected by TEV protease cleavage of Cdc23 (Mcm10) in fission yeast. BMC Mol Biol. 2005;6:13. 15941470 - 19.
Ouyang KJ, Woo LL, Ellis NA. Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases. Mech Ageing Dev. 2008 Jul-Aug;129(7-8):425-40. 18430459 - 20.
Bachrati CZ, Hickson ID. RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem J. 2003 Sep 15;374(Pt 3):577-606. 12803543 - 21.
Singleton MR, Dillingham MS, Wigley DB. Structure and mechanism of helicases and nucleic acid translocases. Annu Rev Biochem. 2007;76:23-50. 17506634 - 22.
Killoran MP, Keck JL. Sit down, relax and unwind: structural insights into RecQ helicase mechanisms. Nucleic Acids Res. 2006;34(15):4098-105. 16935877 - 23.
Macris MA, Krejci L, Bussen W, Shimamoto A, Sung P. Biochemical characterization of the RECQ4 protein, mutated in Rothmund-Thomson syndrome. DNA Repair (Amst). 2006 Feb 3;5(2):172-80. 16214424 - 24.
Wu L, Chan KL, Ralf C, Bernstein DA, Garcia PL, Bohr VA, Vindigni A, Janscak P, Keck JL, Hickson ID. The HRDC domain of BLM is required for the dissolution of double Holliday junctions. Embo J. 2005 Jul 20;24(14):2679-87. 15990871 - 25.
Xu X, Rochette PJ, Feyissa EA, Su TV, Liu Y. MCM10 mediates RECQ4 association with MCM2-7 helicase complex during DNA replication. Embo J. 2009 Oct 7;28(19):3005-14. 19696745 - 26.
Chu WK, Hickson ID. RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer. 2009 Sep;9(9):644-54. 19657341 - 27.
Mogni ME, Costa A, Ioannou C, Bell SD. The glutamate switch is present in all seven clades of AAA+ protein. Biochemistry. 2009 Sep 22;48(37):8774-5. 19702328 - 28.
Snider J, Thibault G, Houry WA. The AAA+ superfamily of functionally diverse proteins. Genome Biol. 2008;9(4):216. 18466635 - 29.
Davey MJ, Jeruzalmi D, Kuriyan J, O'Donnell M. Motors and switches: AAA+ machines within the replisome. Nat Rev Mol Cell Biol. 2002 Nov;3(11):826-35. 12415300 - 30.
Ogura T, Wilkinson AJ. AAA+ superfamily ATPases: common structure--diverse function. Genes Cells. 2001 Jul;6(7):575-97. 11473577 - 31.
Saraste M, Sibbald PR, Wittinghofer A. The P-loop--a common motif in ATP- and GTP-binding proteins. Trends Biochem Sci. 1990 Nov;15(11):430-4. 2126155 - 32.
Walker JE, Saraste M, Runswick MJ, Gay NJ. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. Embo J. 1982;1(8):945-51. 6329717 - 33.
Davey MJ, Indiani C, O'Donnell M. Reconstitution of the Mcm2-7p heterohexamer, subunit arrangement, and ATP site architecture. J Biol Chem. 2003 Feb 14;278(7):4491-9. 12480933 - 34.
Schwacha A, Bell SP. Interactions between two catalytically distinct MCM subgroups are essential for coordinated ATP hydrolysis and DNA replication. Mol Cell. 2001 Nov;8(5):1093-104. 11741544 - 35.
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD. Positional cloning of the Werner's syndrome gene. Science. 1996 Apr 12;272(5259):258-62. 8602509 - 36.
Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 1954 Dec;88(6):754-8. 13206391 - 37.
Kitao S, Lindor NM, Shiratori M, Furuichi Y, Shimamoto A. Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products. Genomics. 1999 Nov 1;61(3):268-76. 10552928 - 38.
Siitonen HA, Sotkasiira J, Biervliet M, Benmansour A, Capri Y, Cormier-Daire V, Crandall B, Hannula-Jouppi K, Hennekam R, Herzog D, Keymolen K, Lipsanen-Nyman M, Miny P, Plon SE, Riedl S, Sarkar A, Vargas FR, Verloes A, Wang LL, Kaariainen H, Kestila M. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 2009 Feb;17(2):151-8. 18716613 - 39.
Hanada K, Hickson ID. Molecular genetics of RecQ helicase disorders. Cell Mol Life Sci. 2007 Sep;64(17):2306-22. 17571213 - 40.
Karow JK, Wu L, Hickson ID. RecQ family helicases: roles in cancer and aging. Curr Opin Genet Dev. 2000 Feb;10(1):32-8. 10679384 - 41.
German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore). 1993 Nov;72(6):393-406. 8231788 - 42.
German J. Bloom's syndrome. Dermatol Clin. 1995 Jan;13(1):7-18. 7712653 - 43.
Shen JC, Loeb LA. The Werner syndrome gene: the molecular basis of RecQ helicase-deficiency diseases. Trends Genet. 2000 May;16(5):213-20. 10782115 - 44.
Vasseur F, Delaporte E, Zabot MT, Sturque MN, Barrut D, Savary JB, Thomas L, Thomas P. Excision repair defect in Rothmund Thomson syndrome. Acta Derm Venereol. 1999 Mar;79(2):150-2. 10228638 - 45.
Tye BK. MCM proteins in DNA replication. Annu Rev Biochem. 1999;68:649-86. 10872463 - 46.
Forsburg SL. Eukaryotic MCM proteins: beyond replication initiation. Microbiol Mol Biol Rev. 2004 Mar;68(1):109-31. 15007098 - 47.
Chong JP, Hayashi MK, Simon MN, Xu RM, Stillman B. A double-hexamer archaeal minichromosome maintenance protein is an ATP-dependent DNA helicase. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1530-5. 10677495 - 48.
Kelman Z, Lee JK, Hurwitz J. The single minichromosome maintenance protein of Methanobacterium thermoautotrophicum DeltaH contains DNA helicase activity. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14783-8. 10611290 - 49.
Tye BK. Insights into DNA replication from the third domain of life. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2399-401. 10716976 - 50.
Madine MA, Swietlik M, Pelizon C, Romanowski P, Mills AD, Laskey RA. The roles of the MCM, ORC, and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol. 2000 Apr;129(2-3):198-210. 10806069 - 51.
Romanowski P, Madine MA, Rowles A, Blow JJ, Laskey RA. The Xenopus origin recognition complex is essential for DNA replication and MCM binding to chromatin. Curr Biol. 1996 Nov 1;6(11):1416-25. 8939603 - 52.
Blow JJ, Hodgson B. Replication licensing--defining the proliferative state? Trends Cell Biol. 2002 Feb;12(2):72-8. 11849970 - 53.
Madine MA, Khoo CY, Mills AD, Musahl C, Laskey RA. The nuclear envelope prevents reinitiation of replication by regulating the binding of MCM3 to chromatin in Xenopus egg extracts. Curr Biol. 1995 Nov 1;5(11):1270-9. 8574584 - 54.
Ishimi Y. A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J Biol Chem. 1997 Sep 26;272(39):24508-13. 9305914 - 55.
Lee JK, Hurwitz J. Processive DNA helicase activity of the minichromosome maintenance proteins 4, 6, and 7 complex requires forked DNA structures. Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):54-9. 11136247 - 56.
Bochman ML, Schwacha A. The Mcm2-7 complex has in vitro helicase activity. Mol Cell. 2008 Jul 25;31(2):287-93. 18657510 - 57.
Boos D, Frigola J, Diffley JF. Activation of the replicative DNA helicase: breaking up is hard to do. Curr Opin Cell Biol. 2012 Jun;24(3):423-30. 22424671 - 58.
Kang YH, Galal WC, Farina A, Tappin I, Hurwitz J. Properties of the human Cdc45/Mcm2-7/GINS helicase complex and its action with DNA polymerase epsilon in rolling circle DNA synthesis. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6042-7. 22474384 - 59.
Kinoshita Y, Johnson EM. Site-specific loading of an MCM protein complex in a DNA replication initiation zone upstream of the c-MYC gene in the HeLa cell cycle. J Biol Chem. 2004 Aug 20;279(34):35879-89. 15190069 - 60.
Schepers A, Diffley JF. Mutational analysis of conserved sequence motifs in the budding yeast Cdc6 protein. J Mol Biol. 2001 May 11;308(4):597-608. 11350163 - 61.
Nevis KR, Cordeiro-Stone M, Cook JG. Origin licensing and p53 status regulate Cdk2 activity during G(1). Cell Cycle. 2009 Jun 15;8(12):1952-63. 19440053 - 62.
Coverley D, Pelizon C, Trewick S, Laskey RA. Chromatin-bound Cdc6 persists in S and G2 phases in human cells, while soluble Cdc6 is destroyed in a cyclin A-cdk2 dependent process. J Cell Sci. 2000 Jun;113 ( Pt 11):1929-38. 10806104 - 63.
Alexandrow MG, Hamlin JL. Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A. Mol Cell Biol. 2004 Feb;24(4):1614-27. 14749377 - 64.
Shin JH, Grabowski B, Kasiviswanathan R, Bell SD, Kelman Z. Regulation of minichromosome maintenance helicase activity by Cdc6. J Biol Chem. 2003 Sep 26;278(39):38059-67. 12837750 - 65.
Daniel DC, Johnson EM. Addressing the enigma of MCM8 in DNA replication. In: Kušić-Tišma J, ed. Fundamental Aspects of DNA Replication: INTECH 2011:37-52. DOI: 10.5772/21177. http://www.intechopen.com/books/fundamental-aspects-of-dna-replication/addressing-the-enigma-of-mcm8-in-dna-replication - 66.
Forsburg SL. The MCM helicase: linking checkpoints to the replication fork. Biochem Soc Trans. 2008 Feb;36(Pt 1):114-9. 18208397 - 67.
Masai H, You Z, Arai K. Control of DNA replication: regulation and activation of eukaryotic replicative helicase, MCM. IUBMB Life. 2005 Apr-May;57(4-5):323-35. 16036617 - 68.
Costa A, Onesti S. The MCM complex: (just) a replicative helicase? Biochem Soc Trans. 2008 Feb;36(Pt 1):136-40. 18208401 - 69.
Brewster AS, Wang G, Yu X, Greenleaf WB, Carazo JM, Tjajadi M, Klein MG, Chen XS. Crystal structure of a near-full-length archaeal MCM: functional insights for an AAA+ hexameric helicase. Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20191-6. 19073923 - 70.
Makarova KS, Koonin EV, Kelman Z. The CMG (CDC45/RecJ, MCM, GINS) complex is a conserved component of the DNA replication system in all archaea and eukaryotes. Biol Direct. 2012;7:7. 22329974 - 71.
Woodward AM, Gohler T, Luciani MG, Oehlmann M, Ge X, Gartner A, Jackson DA, Blow JJ. Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol. 2006 Jun 5;173(5):673-83. 16754955 - 72.
Claycomb JM, MacAlpine DM, Evans JG, Bell SP, Orr-Weaver TL. Visualization of replication initiation and elongation in Drosophila. J Cell Biol. 2002 Oct 28;159(2):225-36. 12403810 - 73.
Hirai K, Shirakata M. Replication licensing of the EBV oriP minichromosome. Curr Top Microbiol Immunol. 2001;258:13-33. 11443858 - 74.
Yankulov K, Todorov I, Romanowski P, Licatalosi D, Cilli K, McCracken S, Laskey R, Bentley DL. MCM proteins are associated with RNA polymerase II holoenzyme. Mol Cell Biol. 1999 Sep;19(9):6154-63. 10454562 - 75.
Volkening M, Hoffmann I. Involvement of human MCM8 in prereplication complex assembly by recruiting hcdc6 to chromatin. Mol Cell Biol. 2005 Feb;25(4):1560-8. 15684404 - 76.
Klotz-Noack K, Blow JJ. A role for dormant origins in tumor suppression. Mol Cell. 2011 Mar 4;41(5):495-6. 21362544 - 77.
Gomez EB, Catlett MG, Forsburg SL. Different phenotypes in vivo are associated with ATPase motif mutations in Schizosaccharomyces pombe minichromosome maintenance proteins. Genetics. 2002 Apr;160(4):1305-18. 11973289 - 78.
You Z, Komamura Y, Ishimi Y. Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity. Mol Cell Biol. 1999 Dec;19(12):8003-15. 10567526 - 79.
Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, Picard C, Trouillet C, Eidenschenk C, Aoufouchi S, Alcais A, Smith O, Geissmann F, Feighery C, Abel L, Smogorzewska A, Stillman B, Vivier E, Casanova JL, Jouanguy E. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest. 2012 Mar 1;122(3):821-32. 22354167 - 80.
Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, Costigan C, Clark AJ, Metherell LA. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012 Mar 1;122(3):814-20. 22354170 - 81.
Chatrath P, Scott IS, Morris LS, Davies RJ, Rushbrook SM, Bird K, Vowler SL, Grant JW, Saeed IT, Howard D, Laskey RA, Coleman N. Aberrant expression of minichromosome maintenance protein-2 and Ki67 in laryngeal squamous epithelial lesions. Br J Cancer. 2003 Sep 15;89(6):1048-54. 12966424 - 82.
Davidson EJ, Morris LS, Scott IS, Rushbrook SM, Bird K, Laskey RA, Wilson GE, Kitchener HC, Coleman N, Stern PL. Minichromosome maintenance (Mcm) proteins, cyclin B1 and D1, phosphohistone H3 and in situ DNA replication for functional analysis of vulval intraepithelial neoplasia. Br J Cancer. 2003 Jan 27;88(2):257-62. 12610511 - 83.
Freeman A, Morris LS, Mills AD, Stoeber K, Laskey RA, Williams GH, Coleman N. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res. 1999;5(8):2121-32. - 84.
Gonzalez MA, Pinder SE, Callagy G, Vowler SL, Morris LS, Bird K, Bell JA, Laskey RA, Coleman N. Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer. J Clin Oncol. 2003 Dec 1;21(23):4306-13. 14645419 - 85.
Hunt DP, Freeman A, Morris LS, Burnet NG, Bird K, Davies TW, Laskey RA, Coleman N. Early recurrence of benign meningioma correlates with expression of mini-chromosome maintenance-2 protein. Br J Neurosurg. 2002 Feb;16(1):10-5. 11928726 - 86.
Khalili K, Del Valle L, Muralidharan V, Gault WJ, Darbinian N, Otte J, Meier E, Johnson EM, Daniel DC, Kinoshita Y, Amini S, Gordon J. Puralpha Is Essential for Postnatal Brain Development and Developmentally Coupled Cellular Proliferation As Revealed by Genetic Inactivation in the Mouse. Mol Cell Biol. 2003 Oct 1;23(19):6857-75. 12972605 - 87.
Bergemann AD, Johnson EM. The HeLa Pur factor binds single-stranded DNA at a specific element conserved in gene flanking regions and origins of DNA replication. Mol Cell Biol. 1992;12:1257-65. - 88.
Liu W, Pucci B, Rossi M, Pisani FM, Ladenstein R. Structural analysis of the Sulfolobus solfataricus MCM protein N-terminal domain. Nucleic Acids Res. 2008 Jun;36(10):3235-43. 18417534 - 89.
Rong SB, Valiaho J, Vihinen M. Structural basis of Bloom syndrome (BS) causing mutations in the BLM helicase domain. Mol Med. 2000 Mar;6(3):155-64. 10965492 - 90.
Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993 Apr 22;362(6422):709-15. 8469282 - 91.
Sun H, Karow JK, Hickson ID, Maizels N. The Bloom's syndrome helicase unwinds G4 DNA. J Biol Chem. 1998 Oct 16;273(42):27587-92. 9765292 - 92.
Huber MD, Lee DC, Maizels N. G4 DNA unwinding by BLM and Sgs1p: substrate specificity and substrate-specific inhibition. Nucleic Acids Res. 2002 Sep 15;30(18):3954-61. 12235379 - 93.
van Brabant AJ, Ye T, Sanz M, German IJ, Ellis NA, Holloman WK. Binding and melting of D-loops by the Bloom syndrome helicase. Biochemistry. 2000 Nov 28;39(47):14617-25. 11087418 - 94.
Karow JK, Constantinou A, Li JL, West SC, Hickson ID. The Bloom's syndrome gene product promotes branch migration of holliday junctions. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6504-8. 10823897 - 95.
Wu L, Hickson ID. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature. 2003 Dec 18;426(6968):870-4. 14685245 - 96.
Hand R, German J. A retarded rate of DNA chain growth in Bloom's syndrome. Proc Natl Acad Sci U S A. 1975 Feb;72(2):758-62. 1054854 - 97.
Lonn U, Lonn S, Nylen U, Winblad G, German J. An abnormal profile of DNA replication intermediates in Bloom's syndrome. Cancer Res. 1990 Jun 1;50(11):3141-5. 2110504 - 98.
Han H, Hurley LH. G-quadruplex DNA: a potential target for anti-cancer drug design. Trends Pharmacol Sci. 2000 Apr;21(4):136-42. 10740289 - 99.
Davies SL, North PS, Hickson ID. Role for BLM in replication-fork restart and suppression of origin firing after replicative stress. Nat Struct Mol Biol. 2007 Jul;14(7):677-9. 17603497 - 100.
Rao VA, Conti C, Guirouilh-Barbat J, Nakamura A, Miao ZH, Davies SL, Sacca B, Hickson ID, Bensimon A, Pommier Y. Endogenous gamma-H2AX-ATM-Chk2 checkpoint activation in Bloom's syndrome helicase deficient cells is related to DNA replication arrested forks. Mol Cancer Res. 2007 Jul;5(7):713-24. 17634426 - 101.
Sengupta S, Linke SP, Pedeux R, Yang Q, Farnsworth J, Garfield SH, Valerie K, Shay JW, Ellis NA, Wasylyk B, Harris CC. BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. Embo J. 2003 Mar 3;22(5):1210-22. 12606585 - 102.
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000 Apr 15;14(8):927-39. 10783165 - 103.
Davies SL, North PS, Dart A, Lakin ND, Hickson ID. Phosphorylation of the Bloom's syndrome helicase and its role in recovery from S-phase arrest. Mol Cell Biol. 2004 Feb;24(3):1279-91. 14729972 - 104.
Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC. Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. J Cell Biol. 2004 Sep 13;166(6):801-13. 15364958 - 105.
Brosh RM, Jr., Driscoll HC, Dianov GL, Sommers JA. Biochemical characterization of the WRN-FEN-1 functional interaction. Biochemistry. 2002 Oct 8;41(40):12204-16. 12356323 - 106.
Kao HI, Veeraraghavan J, Polaczek P, Campbell JL, Bambara RA. On the roles of Saccharomyces cerevisiae Dna2p and Flap endonuclease 1 in Okazaki fragment processing. J Biol Chem. 2004 Apr 9;279(15):15014-24. 14747468 - 107.
Bartos JD, Wang W, Pike JE, Bambara RA. Mechanisms by which Bloom protein can disrupt recombination intermediates of Okazaki fragment maturation. J Biol Chem. 2006 Oct 27;281(43):32227-39. 16950766 - 108.
Sharma S, Otterlei M, Sommers JA, Driscoll HC, Dianov GL, Kao HI, Bambara RA, Brosh RM, Jr. WRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork. Mol Biol Cell. 2004 Feb;15(2):734-50. 14657243 - 109.
Sharma S, Sommers JA, Gary RK, Friedrich-Heineken E, Hubscher U, Brosh RM, Jr. The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Nucleic Acids Res. 2005;33(21):6769-81. 16326861 - 110.
Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM, Jr. Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. J Biol Chem. 2004 Mar 12;279(11):9847-56. 14688284 - 111.
Bachrati CZ, Borts RH, Hickson ID. Mobile D-loops are a preferred substrate for the Bloom's syndrome helicase. Nucleic Acids Res. 2006;34(8):2269-79. 16670433 - 112.
Bugreev DV, Yu X, Egelman EH, Mazin AV. Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. Genes Dev. 2007 Dec 1;21(23):3085-94. 18003860 - 113.
Bugreev DV, Brosh RM, Jr., Mazin AV. RECQ1 possesses DNA branch migration activity. J Biol Chem. 2008 Jul 18;283(29):20231-42. 18495662 - 114.
Jiao R, Bachrati CZ, Pedrazzi G, Kuster P, Petkovic M, Li JL, Egli D, Hickson ID, Stagljar I. Physical and functional interaction between the Bloom's syndrome gene product and the largest subunit of chromatin assembly factor 1. Mol Cell Biol. 2004 Jun;24(11):4710-9. 15143166 - 115.
von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM, Jr., Hickson ID, Bohr VA. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. J Biol Chem. 2002 Jun 14;277(24):22035-44. 11919194 - 116.
Brosh RM, Jr., Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA. Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity. J Biol Chem. 2000 Aug 4;275(31):23500-8. 10825162 - 117.
Brosh RM, Jr., Orren DK, Nehlin JO, Ravn PH, Kenny MK, Machwe A, Bohr VA. Functional and physical interaction between WRN helicase and human replication protein A. J Biol Chem. 1999 Jun 25;274(26):18341-50. 10373438 - 118.
Shen JC, Gray MD, Oshima J, Loeb LA. Characterization of Werner syndrome protein DNA helicase activity: directionality, substrate dependence and stimulation by replication protein A. Nucleic Acids Res. 1998 Jun 15;26(12):2879-85. 9611231 - 119.
Blander G, Kipnis J, Leal JF, Yu CE, Schellenberg GD, Oren M. Physical and functional interaction between p53 and the Werner's syndrome protein. J Biol Chem. 1999 Oct 8;274(41):29463-9. 10506209 - 120.
Spillare EA, Robles AI, Wang XW, Shen JC, Yu CE, Schellenberg GD, Harris CC. p53-mediated apoptosis is attenuated in Werner syndrome cells. Genes Dev. 1999 Jun 1;13(11):1355-60. 10364153 - 121.
Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC. Functional interaction of p53 and BLM DNA helicase in apoptosis. J Biol Chem. 2001 Aug 31;276(35):32948-55. 11399766 - 122.
Walpita D, Plug AW, Neff NF, German J, Ashley T. Bloom's syndrome protein, BLM, colocalizes with replication protein A in meiotic prophase nuclei of mammalian spermatocytes. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5622-7. 10318934 - 123.
Li JL, Harrison RJ, Reszka AP, Brosh RM, Jr., Bohr VA, Neidle S, Hickson ID. Inhibition of the Bloom's and Werner's syndrome helicases by G-quadruplex interacting ligands. Biochemistry. 2001 Dec 18;40(50):15194-202. 11735402 - 124.
Popuri V, Bachrati CZ, Muzzolini L, Mosedale G, Costantini S, Giacomini E, Hickson ID, Vindigni A. The Human RecQ helicases, BLM and RECQ1, display distinct DNA substrate specificities. J Biol Chem. 2008 Jun 27;283(26):17766-76. 18448429 - 125.
Poot M, Hoehn H, Runger TM, Martin GM. Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines. Exp Cell Res. 1992 Oct;202(2):267-73. 1327851 - 126.
Chan KL, North PS, Hickson ID. BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. Embo J. 2007 Jul 25;26(14):3397-409. 17599064 - 127.
Baumann C, Korner R, Hofmann K, Nigg EA. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell. 2007 Jan 12;128(1):101-14. 17218258 - 128.
Johnson FB, Lombard DB, Neff NF, Mastrangelo MA, Dewolf W, Ellis NA, Marciniak RA, Yin Y, Jaenisch R, Guarente L. Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells. Cancer Res. 2000 Mar 1;60(5):1162-7. 10728666 - 129.
Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID. The Bloom's syndrome gene product interacts with topoisomerase III. J Biol Chem. 2000 Mar 31;275(13):9636-44. 10734115 - 130.
Bussen W, Raynard S, Busygina V, Singh AK, Sung P. Holliday junction processing activity of the BLM-Topo IIIalpha-BLAP75 complex. J Biol Chem. 2007 Oct 26;282(43):31484-92. 17728255 - 131.
Raynard S, Zhao W, Bussen W, Lu L, Ding YY, Busygina V, Meetei AR, Sung P. Functional role of BLAP75 in BLM-topoisomerase IIIalpha-dependent holliday junction processing. J Biol Chem. 2008 Jun 6;283(23):15701-8. 18390547 - 132.
Wu L, Bachrati CZ, Ou J, Xu C, Yin J, Chang M, Wang W, Li L, Brown GW, Hickson ID. BLAP75/RMI1 promotes the BLM-dependent dissolution of homologous recombination intermediates. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4068-73. 16537486 - 133.
Singh TR, Ali AM, Busygina V, Raynard S, Fan Q, Du CH, Andreassen PR, Sung P, Meetei AR. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome. Genes Dev. 2008 Oct 15;22(20):2856-68. 18923083 - 134.
Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H, Dorn T, Spiegel R, Oral EA, Abid M, Battisti C, Lucci-Cordisco E, Neri G, Steed EH, Kidd A, Isley W, Showalter D, Vittone JL, Konstantinow A, Ring J, Meyer P, Wenger SL, von Herbay A, Wollina U, Schuelke M, Huizenga CR, Leistritz DF, Martin GM, Mian IS, Oshima J. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat. 2006 Jun;27(6):558-67. 16673358 - 135.
Davis T, Singhrao SK, Wyllie FS, Haughton MF, Smith PJ, Wiltshire M, Wynford-Thomas D, Jones CJ, Faragher RG, Kipling D. Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms. J Cell Sci. 2003 Apr 1;116(Pt 7):1349-57. 12615976 - 136.
Epstein CJ, Martin GM, Schultz AL, Motulsky AG. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore). 1966 May;45(3):177-221. 5327241 - 137.
Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall S. The gene responsible for Werner syndrome may be a cell division "counting" gene. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12030-4. 8265666 - 138.
Schulz VP, Zakian VA, Ogburn CE, McKay J, Jarzebowicz AA, Edland SD, Martin GM. Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells. Hum Genet. 1996 Jun;97(6):750-4. 8641691 - 139.
Tahara H, Tokutake Y, Maeda S, Kataoka H, Watanabe T, Satoh M, Matsumoto T, Sugawara M, Ide T, Goto M, Furuichi Y, Sugimoto M. Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein-Barr virus. Oncogene. 1997 Oct 16;15(16):1911-20. 9365237 - 140.
Sandell LL, Zakian VA. Loss of a yeast telomere: arrest, recovery, and chromosome loss. Cell. 1993 Nov 19;75(4):729-39. 8242745 - 141.
Nurnberg P, Thiel G, Weber F, Epplen JT. Changes of telomere lengths in human intracranial tumours. Hum Genet. 1993 Mar;91(2):190-2. 8462979 - 142.
Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999 May 14;97(4):503-14. 10338214 - 143.
Murti KG, Prescott DM. Telomeres of polytene chromosomes in a ciliated protozoan terminate in duplex DNA loops. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14436-9. 10588723 - 144.
Williamson JR, Raghuraman MK, Cech TR. Monovalent cation-induced structure of telomeric DNA: the G-quartet model. Cell. 1989 Dec 1;59(5):871-80. 2590943 - 145.
Crabbe L, Verdun RE, Haggblom CI, Karlseder J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science. 2004 Dec 10;306(5703):1951-3. 15591207 - 146.
Hyun M, Bohr VA, Ahn B. Biochemical characterization of the WRN-1 RecQ helicase of Caenorhabditis elegans. Biochemistry. 2008 Jul 15;47(28):7583-93. 18558712 - 147.
Constantinou A, Tarsounas M, Karow JK, Brosh RM, Bohr VA, Hickson ID, West SC. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. EMBO Rep. 2000 Jul;1(1):80-4. 11256630 - 148.
Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D, Bohr VA. Ku complex interacts with and stimulates the Werner protein. Genes Dev. 2000 Apr 15;14(8):907-12. 10783163 - 149.
Opresko PL, Otterlei M, Graakjaer J, Bruheim P, Dawut L, Kolvraa S, May A, Seidman MM, Bohr VA. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol Cell. 2004 Jun 18;14(6):763-74. 15200954 - 150.
Bhattacharyya S, Sandy A, Groden J. Unwinding protein complexes in ALTernative telomere maintenance. J Cell Biochem. 2010 2010;109(1):7-15. 19911388 - 151.
Huang S, Li B, Gray MD, Oshima J, Mian IS, Campisi J. The premature ageing syndrome protein, WRN, is a 3'-->5' exonuclease. Nat Genet. 1998 Oct;20(2):114-6. 9771700 - 152.
Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA. Functional interaction between the Werner Syndrome protein and DNA polymerase delta. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4603-8. 10781066 - 153.
Shen JC, Gray MD, Oshima J, Kamath-Loeb AS, Fry M, Loeb LA. Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide. J Biol Chem. 1998 Dec 18;273(51):34139-44. 9852073 - 154.
Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J. Characterization of the human and mouse WRN 3'-->5' exonuclease. Nucleic Acids Res. 2000 Jun 15;28(12):2396-405. 10871373 - 155.
Kamath-Loeb AS, Shen JC, Loeb LA, Fry M. Werner syndrome protein. II. Characterization of the integral 3' --> 5' DNA exonuclease. J Biol Chem. 1998 Dec 18;273(51):34145-50. 9852074 - 156.
Shen JC, Loeb LA. Werner syndrome exonuclease catalyzes structure-dependent degradation of DNA. Nucleic Acids Res. 2000 Sep 1;28(17):3260-8. 10954593 - 157.
Lebel M, Spillare EA, Harris CC, Leder P. The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem. 1999 Dec 31;274(53):37795-9. 10608841 - 158.
Prince PR, Emond MJ, Monnat RJ, Jr. Loss of Werner syndrome protein function promotes aberrant mitotic recombination. Genes Dev. 2001 Apr 15;15(8):933-8. 11316787 - 159.
Bischof O, Kim SH, Irving J, Beresten S, Ellis NA, Campisi J. Regulation and localization of the Bloom syndrome protein in response to DNA damage. J Cell Biol. 2001 Apr 16;153(2):367-80. 11309417 - 160.
Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Gueret M. Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase. Oncogene. 2000 May 25;19(23):2731-8. 10851073 - 161.
Sanz MM, Proytcheva M, Ellis NA, Holloman WK, German J. BLM, the Bloom's syndrome protein, varies during the cell cycle in its amount, distribution, and co-localization with other nuclear proteins. Cytogenet Cell Genet. 2000;91(1-4):217-23. 11173860 - 162.
Zhong S, Hu P, Ye TZ, Stan R, Ellis NA, Pandolfi PP. A role for PML and the nuclear body in genomic stability. Oncogene. 1999 Dec 23;18(56):7941-7. 10637504 - 163.
Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG, Bazett-Jones DP. Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR. J Cell Biol. 2006 Oct 9;175(1):55-66. 17030982 - 164.
Matunis MJ, Zhang XD, Ellis NA. SUMO: the glue that binds. Dev Cell. 2006 Nov;11(5):596-7. 17084352 - 165.
Johnson ES. Protein modification by SUMO. Annu Rev Biochem. 2004;73:355-82. 15189146 - 166.
Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP. The mechanisms of PML-nuclear body formation. Mol Cell. 2006 Nov 3;24(3):331-9. 17081985 - 167.
Eladad S, Ye TZ, Hu P, Leversha M, Beresten S, Matunis MJ, Ellis NA. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Hum Mol Genet. 2005 May 15;14(10):1351-65. 15829507 - 168.
Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA. Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability. Hum Mol Genet. 2001 Jun 1;10(12):1287-98. 11406610 - 169.
Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 2000 Jul 27-Aug 10;10(15):886-95. 10959836 - 170.
Pilch DR, Sedelnikova OA, Redon C, Celeste A, Nussenzweig A, Bonner WM. Characteristics of gamma-H2AX foci at DNA double-strand breaks sites. Biochem Cell Biol. 2003 Jun;81(3):123-9. 12897845 - 171.
Rogakou EP, Boon C, Redon C, Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 1999 Sep 6;146(5):905-16. 10477747 - 172.
Bassing CH, Alt FW. H2AX may function as an anchor to hold broken chromosomal DNA ends in close proximity. Cell Cycle. 2004 Feb;3(2):149-53. 14712078 - 173.
Davalos AR, Campisi J. Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks. J Cell Biol. 2003 Sep 29;162(7):1197-209. 14517203 - 174.
Beamish H, Kedar P, Kaneko H, Chen P, Fukao T, Peng C, Beresten S, Gueven N, Purdie D, Lees-Miller S, Ellis N, Kondo N, Lavin MF. Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM. J Biol Chem. 2002 Aug 23;277(34):30515-23. 12034743 - 175.
Franchitto A, Pichierri P. Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest. J Cell Biol. 2002 Apr 1;157(1):19-30. 11916980 - 176.
Raderschall E, Golub EI, Haaf T. Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1921-6. 10051570 - 177.
Adams MD, McVey M, Sekelsky JJ. Drosophila BLM in double-strand break repair by synthesis-dependent strand annealing. Science. 2003 Jan 10;299(5604):265-7. 12522255 - 178.
Plank JL, Wu J, Hsieh TS. Topoisomerase IIIalpha and Bloom's helicase can resolve a mobile double Holliday junction substrate through convergent branch migration. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11118-23. 16849422 - 179.
Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J. The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair. J Biol Chem. 2001 Aug 10;276(32):30031-5. 11325959 - 180.
Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I. Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Res. 2001 Nov 1;29(21):4378-86. 11691925 - 181.
Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol. 2003 May;23(10):3417-26. 12724401 - 182.
Yin J, Sobeck A, Xu C, Meetei AR, Hoatlin M, Li L, Wang W. BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity. Embo J. 2005 Apr 6;24(7):1465-76. 15775963 - 183.
Machwe A, Xiao L, Lloyd RG, Bolt E, Orren DK. Replication fork regression in vitro by the Werner syndrome protein (WRN): holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity. Nucleic Acids Res. 2007;35(17):5729-47. 17717003 - 184.
Crabbe L, Jauch A, Naeger CM, Holtgreve-Grez H, Karlseder J. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2205-10. 17284601 - 185.
de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005 Sep 15;19(18):2100-10. 16166375 - 186.
Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J Biol Chem. 2002 Oct 25;277(43):41110-9. 12181313 - 187.
Opresko PL, Mason PA, Podell ER, Lei M, Hickson ID, Cech TR, Bohr VA. POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. J Biol Chem. 2005 Sep 16;280(37):32069-80. 16030011 - 188.
Kao HI, Campbell JL, Bambara RA. Dna2p helicase/nuclease is a tracking protein, like FEN1, for flap cleavage during Okazaki fragment maturation. J Biol Chem. 2004 Dec 3;279(49):50840-9. 15448135 - 189.
Sharma S, Sommers JA, Brosh RM, Jr. In vivo function of the conserved non-catalytic domain of Werner syndrome helicase in DNA replication. Hum Mol Genet. 2004 Oct 1;13(19):2247-61. 15282207 - 190.
Szekely AM, Chen YH, Zhang C, Oshima J, Weissman SM. Werner protein recruits DNA polymerase delta to the nucleolus. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11365-70. 11027336 - 191.
Kamath-Loeb AS, Loeb LA, Johansson E, Burgers PM, Fry M. Interactions 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. J Biol Chem. 2001 May 11;276(19):16439-46. 11279038 - 192.
Fry M, Loeb LA. Human werner syndrome DNA helicase unwinds tetrahelical structures of the fragile X syndrome repeat sequence d(CGG)n. J Biol Chem. 1999 Apr 30;274(18):12797-802. 10212265 - 193.
Riha K, Heacock ML, Shippen DE. The role of the nonhomologous end-joining DNA double-strand break repair pathway in telomere biology. Annu Rev Genet. 2006;40:237-77. 16822175 - 194.
Cheng WH, von Kobbe C, Opresko PL, Arthur LM, Komatsu K, Seidman MM, Carney JP, Bohr VA. Linkage between Werner syndrome protein and the Mre11 complex via Nbs1. J Biol Chem. 2004 May 14;279(20):21169-76. 15026416 - 195.
Celli GB, Denchi EL, de Lange T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat Cell Biol. 2006 Aug;8(8):885-90. 16845382 - 196.
Laud PR, Multani AS, Bailey SM, Wu L, Ma J, Kingsley C, Lebel M, Pathak S, DePinho RA, Chang S. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 2005 Nov 1;19(21):2560-70. 16264192 - 197.
Harrigan JA, Wilson DM, 3rd, Prasad R, Opresko PL, Beck G, May A, Wilson SH, Bohr VA. The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta. Nucleic Acids Res. 2006;34(2):745-54. 16449207 - 198.
Blank A, Bobola MS, Gold B, Varadarajan S, D DK, Meade EH, Rabinovitch PS, Loeb LA, Silber JR. The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function. DNA Repair (Amst). 2004 Jun 3;3(6):629-38. 15135730 - 199.
Harrigan JA, Opresko PL, von Kobbe C, Kedar PS, Prasad R, Wilson SH, Bohr VA. The Werner syndrome protein stimulates DNA polymerase beta strand displacement synthesis via its helicase activity. J Biol Chem. 2003 Jun 20;278(25):22686-95. 12665521 - 200.
Li B, Navarro S, Kasahara N, Comai L. Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1. J Biol Chem. 2004 Apr 2;279(14):13659-67. 14734561 - 201.
von Kobbe C, Harrigan JA, Schreiber V, Stiegler P, Piotrowski J, Dawut L, Bohr VA. Poly(ADP-ribose) polymerase 1 regulates both the exonuclease and helicase activities of the Werner syndrome protein. Nucleic Acids Res. 2004;32(13):4003-14. 15292449 - 202.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14;434(7035):913-7. 15829966 - 203.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14;434(7035):917-21. 15829967 - 204.
Bohr VA, Souza Pinto N, Nyaga SG, Dianov G, Kraemer K, Seidman MM, Brosh RM, Jr. DNA repair and mutagenesis in Werner syndrome. Environ Mol Mutagen. 2001;38(2-3):227-34. 11746759 - 205.
Yun J, Zhong Q, Kwak JY, Lee WH. Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest. Oncogene. 2005 Jun 9;24(25):4009-16. 15782115 - 206.
Cheng WH, Kusumoto R, Opresko PL, Sui X, Huang S, Nicolette ML, Paull TT, Campisi J, Seidman M, Bohr VA. Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links. Nucleic Acids Res. 2006;34(9):2751-60. 16714450 - 207.
Mann MB, Hodges CA, Barnes E, Vogel H, Hassold TJ, Luo G. Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome. Hum Mol Genet. 2005 Mar 15;14(6):813-25. 15703196 - 208.
Sangrithi MN, Bernal JA, Madine M, Philpott A, Lee J, Dunphy WG, Venkitaraman AR. Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome. Cell. 2005 Jun 17;121(6):887-98. 15960976 - 209.
Matsuno K, Kumano M, Kubota Y, Hashimoto Y, Takisawa H. The N-terminal noncatalytic region of Xenopus RecQ4 is required for chromatin binding of DNA polymerase alpha in the initiation of DNA replication. Mol Cell Biol. 2006 Jul;26(13):4843-52. 16782873 - 210.
Im JS, Ki SH, Farina A, Jung DS, Hurwitz J, Lee JK. Assembly of the Cdc45-Mcm2-7-GINS complex in human cells requires the Ctf4/And-1, RecQL4, and Mcm10 proteins. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15628-32. 19805216 - 211.
Kumata Y, Tada S, Yamanada Y, Tsuyama T, Kobayashi T, Dong YP, Ikegami K, Murofushi H, Seki M, Enomoto T. Possible involvement of RecQL4 in the repair of double-strand DNA breaks in Xenopus egg extracts. Biochim Biophys Acta. 2007 Apr;1773(4):556-64. 17320201 - 212.
Petkovic M, Dietschy T, Freire R, Jiao R, Stagljar I. The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability. J Cell Sci. 2005 Sep 15;118(Pt 18):4261-9. 16141230 - 213.
Woo LL, Futami K, Shimamoto A, Furuichi Y, Frank KM. The Rothmund-Thomson gene product RECQL4 localizes to the nucleolus in response to oxidative stress. Exp Cell Res. 2006 Oct 15;312(17):3443-57. 16949575 - 214.
Werner SR, Prahalad AK, Yang J, Hock JM. RECQL4-deficient cells are hypersensitive to oxidative stress/damage: Insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome. Biochem Biophys Res Commun. 2006 Jun 23;345(1):403-9. 16678792 - 215.
Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, Iliakis G. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res. 2006;34(21):6170-82. 17088286 - 216.
Audebert M, Salles B, Calsou P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem. 2004 Dec 31;279(53):55117-26. 15498778 - 217.
Bailis JM, Luche DD, Hunter T, Forsburg SL. Minichromosome maintenance proteins interact with checkpoint and recombination proteins to promote s-phase genome stability. Mol Cell Biol. 2008 Mar;28(5):1724-38. 18180284 - 218.
Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F, Edmondson RD, Labib K. GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol. 2006 Apr;8(4):358-66. 16531994 - 219.
Katou Y, Kanoh Y, Bando M, Noguchi H, Tanaka H, Ashikari T, Sugimoto K, Shirahige K. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature. 2003 Aug 28;424(6952):1078-83. 12944972 - 220.
Calzada A, Hodgson B, Kanemaki M, Bueno A, Labib K. Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev. 2005 Aug 15;19(16):1905-19. 16103218 - 221.
Komata M, Bando M, Araki H, Shirahige K. The direct binding of Mrc1, a checkpoint mediator, to Mcm6, a replication helicase, is essential for the replication checkpoint against methyl methanesulfonate-induced stress. Mol Cell Biol. 2009 Sep;29(18):5008-19. 19620285 - 222.
Nedelcheva MN, Roguev A, Dolapchiev LB, Shevchenko A, Taskov HB, Shevchenko A, Stewart AF, Stoynov SS. Uncoupling of unwinding from DNA synthesis implies regulation of MCM helicase by Tof1/Mrc1/Csm3 checkpoint complex. J Mol Biol. 2005 Apr 1;347(3):509-21. 15755447 - 223.
Lou H, Komata M, Katou Y, Guan Z, Reis CC, Budd M, Shirahige K, Campbell JL. Mrc1 and DNA polymerase epsilon function together in linking DNA replication and the S phase checkpoint. Mol Cell. 2008 Oct 10;32(1):106-17. 18851837 - 224.
Szyjka SJ, Viggiani CJ, Aparicio OM. Mrc1 is required for normal progression of replication forks throughout chromatin in S. cerevisiae. Mol Cell. 2005 Sep 2;19(5):691-7. 16137624 - 225.
Alcasabas AA, Osborn AJ, Bachant J, Hu F, Werler PJ, Bousset K, Furuya K, Diffley JF, Carr AM, Elledge SJ. Mrc1 transduces signals of DNA replication stress to activate Rad53. Nat Cell Biol. 2001 Nov;3(11):958-65. 11715016 - 226.
Bjergbaek L, Cobb JA, Tsai-Pflugfelder M, Gasser SM. Mechanistically distinct roles for Sgs1p in checkpoint activation and replication fork maintenance. Embo J. 2005 Jan 26;24(2):405-17. 15616582 - 227.
Bando M, Katou Y, Komata M, Tanaka H, Itoh T, Sutani T, Shirahige K. Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that associates with DNA replication forks. J Biol Chem. 2009 Dec 4;284(49):34355-65. 19819872 - 228.
Pryce DW, Ramayah S, Jaendling A, McFarlane RJ. Recombination at DNA replication fork barriers is not universal and is differentially regulated by Swi1. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4770-5. 19273851