Mammalian ATP-dependent chromatin remodeling complexes identified as taking part in nucleotide excision repair.
The chromatin basic structure named nucleosome contains 147 DNA base pairs wounded 1.65 times around an octamer of histone proteins which consist of two copies of H2A, H2B, H3, and H4, separated by linker regions of 20-110 nucleotides. Nucleosome assembly in the nucleus proceeds in two stages. At first, hetero-tetramer H3/H4 integrates into the DNA and at the second stage the heterodimer H2A/H2B is added. Nucleosomes are further condensed into 30 nm fibers through the incorporation of histone H1, located in the linker regions, achieving an additional 250-fold structural compaction in metaphase chromosomes. Nucleosome packaging restricts protein binding and obstructs DNA-templated reactions. Therefore, local modulation of DNA accessibility is necessary for the fundamental processes of transcription, replication and DNA repair to occur. In this sense, chromatin structure is not static but subject to changes at every level of its hierarchy. Nucleosomes are considered dynamic and instructive particles that are involved in practically all chromosomal processes, being subjected to highly ordered changes considered as epigenetic information, which modulates DNA accessibility [1, 2]. Nucleosomes exhibit three dynamic properties: a) covalent histone post-translational modifications, b) change of composition due to removal of histones and c) movement along DNA. The latter two are carried out by ATP-dependent chromatin remodeling complexes . Histone post-translational modifications (PTMs) such as the addition of acetyl, methyl, phosphate, ubiquitin, and sumo groups change the properties of histones, modifying histone-DNA or histone-histone interactions . Modifying complexes add or remove covalent modifications on particular residues of the N- and C-terminal domains of histone proteins, altering the structure of chromatin and creating “flags” which can be recognized by different regulatory proteins. Many chromatin-associated proteins contain protein domains that bind these moieties such as the bromodomain that recognizes acetylated residues and chromodomains, Tudor, Plant Homeo Domain (PHD) fingers, Malignant brain tumor (MBT) domains that bind to methylated lysines or arginines .
In the regulation of gene expression a “code of histones” has been determined, where different PTMs allow the recruitment of different factors specifying determined functions on chromatin . Certain histone modifications can even induce or inhibit the appearance of other modifications in adjacent aminoacidic residues . ATP-dependent chromatin remodeling factors use ATP hydrolysis to slide or unwrap DNA. These multi-subunit complexes can also catalyze eviction of histone octamers to promote histone variant replacement . Eukaryotic cells also contain alternative versions of the canonical histones, differing in the aminoacidic sequences. One of these isoforms is histone H2AX, which differs from the canonical H2A histone by the presence of a short C-terminal tail. Nucleosomes containing canonical histones are formed during replication, and non-canonical histones replace canonical ones in the course of DNA metabolic processes not associated with replication, such as transcription and repair. Other protein complexes participating in the process of nucleosome assembly/disassembly such as histones chaperones like the chromatin assembly factor 1 (CAF-1), composed by three subunits: p150, p60 and p48, which has been suggested to play a pivotal role in chromatin assembly after DNA replication and repair . During DNA replication, CAF-1 complex binds to newly synthesized histone H3 and H4 and deposits the histone tetramers onto replicating DNA to form the chromatin precursor in a PCNA-dependent manner. The replicated precursor then serves as the template for deposition of either old or new histone H2A and H2B.
In response to both DNA damage and replication stress, a signal transduction cascade known as the checkpoint response is activated. This phenomenon is also referred to as the DNA damage response. It is becoming clear that DNA damage sensors can recognize the chromatin-associated signals of DNA damage. This information is then transmitted via signal transducers, including diffusible protein kinases, to effector molecules such as the checkpoint kinases that mediate the physiological response of the cell to DNA damage, which ultimately promotes efficient repair and cell survival. The primary target of this pathway is the arrest or slowing of the cell cycle, providing time for DNA repair to take place. Depending on the type of DNA damage induced, different repair mechanisms can be activated, such as non-homologous end joining and homologous recombination in case of double strand breaks induction and excision repair mechanisms in case of nucleotide or base damage. As for DNA transcription, a regulatory role of the epigenetic code in DNA repair has been proposed [3, 4, 9, 10]. Chromatin remodeling processes not only influence access to DNA but also serves as a docking site for repair and signaling proteins [7, 10-12]. Chromatin plays a pivotal role in regulating DNA-associated processes and it is itself subject of regulation by the DNA-damage response. In this chapter, we summarize the current knowledge on the involvement of chromatin remodeling processes in nucleotide excision repair in mammalian cells.
2. Chromatin structure after UVC-induced DNA damage
Endogenous and exogenous DNA damaging agents modify DNA. One of the most common environmental stresses that produce lesions in DNA is UV light. UVC irradiation induces cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4PP) which result in an abnormal DNA structure that signals the lesion , [13-15]. However, they can be distributed differently along the chromatin structure. CPDs are mainly found in the minor groove of DNA facing away from the histone surface and 6-4PPs are preferentially formed in linker DNA but can also be seen throughout the histone core region. This indicates that nucleosomes can actually confer partial protection against this type of DNA damage. Moreover, an
Access to these lesions in chromatin can be achieved mainly by the action of ATP-dependent chromatin remodeling factors and the addition of post-translational modifications on histones , which could facilitate their removal. However, like DNA repair enzymes, both chromatin remodeling proteins and histone modification factors require initial localization to damaged sites, but the mechanism by which UVC-damaged DNA in chromatin is recognized by these factors and how damaged from undamaged chromatin can be distinguished remain unclear. A recent study using reconstituted nucleosomes containing DNA with CPDs or 6–4PPs showed that the presence of these lesions does not affect the reconstitution of nucleosomes
3. Nucleotide excision repair in chromatin
Nucleotide excision repair (NER) system is more efficient in naked DNA than in chromatin and it is inhibited by the presence of nucleosomes and heterochromatin, which limit the access of repair proteins to DNA . Thus, for NER to recognize, excise and repair DNA damage efficiently, chromatin needs to be adapted . Therefore, a chromatin rearrangement is a necessary step in the access of repair proteins to DNA damage sites and led to the ‘‘access, repair, restore’’ model of NER in chromatin. This model suggests that early chromatin remodeling steps and/or intrinsic dynamic changes in chromatin may allow the access of repair complexes to damaged sites, followed by restoration of the original nucleosomal organization after DNA repair [1, 22]. In NER, lesions that are located in linker regions are more accessible for binding by the recognizing proteins. A plausible scenario for DNA repair implies that the lesion is recognized and eliminated in the most accessible sites for repair proteins. Therefore, nucleosome modification and initiation of chromatin relaxation around the repair site start at considerable distances from the initiation point of DNA repair. As a result, other lesions, particularly those in the core of nucleosomes, become more accessible. Thus, proteins responsible for recognizing UVC-induced DNA lesions can recognize and bind them even if they are located in the core of the nucleosome [23, 24].
NER removes a wide range of bulky DNA adducts that distort the double helix of DNA, including those induced by UVC. NER system can be divided into two pathways: transcriptional coupled repair (TCR) pathway, that repairs lesions that occur in transcriptionally active genes and global genome repair (GGR) that acts into lesions in non transcribed DNA [1, 25, 26]. Both pathways involves the action of about 20-30 proteins (Figure 1) in a “cut-and-paste-like” mechanism [26, 27] divided in five steps: a) lesion detection; b) recruitment of TFIIH-XPB-XPD complex, which directs DNA unwinding around the damaged nucleotide; c) recruitment of ERCC1- XPF, XPG, XPA and RPA that induce 5’ and 3’ breaks around the lesion and remove the damaged nucleotide; d) DNA synthesis directed by DNA polymerase δ/ε, PCNA and other accessory factors and e) strand ligation (ligase I/III) [1, 26]. Both pathways use the same cellular machinery in all steps except from lesion recognition. At this initial step, in TCR CSA and CSB direct the basic repair machinery to RNA polymerase II stalled at the lesion . On the other hand, in GGR damage site recognition is carried out by XPC-hHR23B and UV-DDB/XPE complexes [13, 25, 29-31]. The defect in one of the NER proteins is the consequence of three rare recessive syndromes: Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and the photosensitive brittle hair disorder trichothiodystrophy (TTD) [26, 31, 32].
Apart from ATP-dependent chromatin remodeling factors and histone modifications, repair factors themselves could cause chromatin rearrangements. Particularly good candidates for this type of function in the NER system are the transcription-coupled repair factor CSB, which has homology to SWI/SNF chromatin remodeling proteins, and the TFIIH complex that contains the helicase subunits XPD and XPB . However, a non-mutually exclusive suggestion is that global chromatin relaxation increases accessibility over the whole genome in response to damage in order to expose the individual damage sites for recognition . After removal of the DNA lesion and completion of new DNA synthesis by DNA polymerase and DNA ligase, the original structure of chromatin is restored by the action of CAF-1 [22, 31]. The recruitment of mammalian CAF-1 is restricted to damaged sites and depends on NER, binding concomitantly with repair synthesis . Chromatin restoration does not simply recycle histones, but also incorporate new histones and histones with distinct post-translational modifications into chromatin. For example, new histone H3.1, deposited during DNA replication, is incorporated into chromatin as a marker of sites of UVC-induced DNA damage repaired by NER .
4. Histone covalent modifications in NER
One of the most important chromatin remodeling processes that occur during NER is histone covalent modification, which constitutes a reversible process. The most frequent histone tail modification is the histone acetylation/deacetylation process, which is controlled by histone acetyltransferases (HAT) and histone deacetylases (HDAC), determining either gene activation or inactivation, respectively. Meanwhile, histone methylation is carried out by histone methyl-transferases (HMT) and histone demethylases (HDM) are used for the reverse reaction. Finally, kinases like ATR are responsible for histone phosphorylation, and histone ubiquitination is driven by histone ubiquitin ligases.
4.1. Histone acetylation
The acetylation of the ε-amino group of lysine (K) side chains is a major histone modiﬁcation involved in numerous cellular processes, such as transcription and DNA repair. Acetylation neutralizes the lysines positive charge and this action may consequently weaken the electrostatic interactions between histones and DNA. Thus, acetylated histones could enhance chromatin accessibility by reducing the attractive force between the nucleosome core and negatively charged DNA. For this reason, histone acetylation is often associated with a more ‘‘open’’ chromatin conformation. UVC irradiation induces global and local changes in chromatin structure in order to increase accessibility for repair proteins and hence a proper NER occurs . Early studies demonstrated that acetylated nucleosomes enhance NER efficiency . In this respect, UVC-induced acetylation of H3 K9 and H4 K16 has been observed [37, 38]. H3 K9 acetylation after UVC irradiation requires the recruitment of the transcription factor E2F1, which interacts with the HAT GCN5. In fact, inactivation of GCN5 in human cells decreases recruitment of NER factors to damaged sites, which demonstrates that GCN5 is important for a timely and efficient NER . Besides, UV-DDB complex (DDB1–DDB2) recruits two HATs, such as CBP/p300 and STAGA (a SAGA-like complex containing GCN5L) [39, 40], whose activities induce chromatin remodeling to allow recruitment of the repair complexes at the UVC-induced damage sites. By the same token, it has also been observed that p33ING2, a member of the inhibitor of growth (ING) family proteins, enhances NER in a p53-dependent manner by inducing chromatin relaxation following UVC irradiation, increased acetylation of histone H4 and recruitment of NER factors to sites of damage . Actually, it has also been observed that CBP/p300 is recruited to UVC damaged sites in a p53-dependent manner via its interaction with CSB, accompanied by an increase in H3 acetylation [34, 42]. Hence, increased histone acetylation at the NER site is likely to contribute to the p53-induced chromatin relaxation that is induced by DNA damage, suggesting that the function of UVC-induced histone acetylation is to promote opening up on the chromatin to facilitate repair. However, employing the
4.2. Histone phosphorylation
The phosphorylation of serine (S), threonine (T), and tyrosine (Y) residues has been documented on all core and most variant histones. Phosphorylation alters the charge of the protein, affecting its ionic properties and inﬂuencing the overall structure and function of the local chromatin environment . Although there is no evidence that PI3K enzymes could be activated by DNA lesions repaired by NER, when DNA replication fork is stalled, NER protein foci are formed, creating single strand breaks (SSBs) which can be covered by RPA/ATRIP and activate the kinase activity of ATR . However, these NER intermediates (SSBs arising from excised lesions) can activate ATR, even outside S-phase . Several histone phosphorylation changes after UVC irradiation have been observed, such as H2AX histone variant which is phosphorylated at S139 (named gamma-H2AX) . H2AX phosphorylation upon UVC in non-S-phase cells depends on ATR and active processing of the lesion by the NER machinery , suggesting that NER-intermediates trigger this response. The notion that gamma-H2AX formation occurs in response to NER and that NER is proficient in H2AX-deficient cells, suggests that this modification mainly plays a role in checkpoint activation during the repair of UVC lesion. Besides, S2, S18 and S122 H2A residues play important roles in survival following UVC exposure . Two aminoacidic residues of histone H3, S10 and T11, appear to be a target of differential phosphorylation during NER. H3 S10 and H3 T11 in mouse are dephosphorylated by UVC irradiation and rephosphorylated after DNA damage repair. Hypophosphorylation of H3 S10 and H3 T11 are associated with transcription repression, and this histone modification might be one of the mechanisms that cells employ to inhibit transcription at UVC-damaged sites .
4.3. Histone methylation
Histone methylation is carried out by a group of enzymes called histone methyltransferases HMT, which covalently modify the lysine and arginine (R) residues of histones by transferring one, two or three methyl groups to the ε-amino group of lysine residues or to the guanidino group of arginine residues . Methylation, unlike acetylation and phosphorylation, does not alter the overall charge of histones. Histone methylation in combination with acetylation creates specific modification signatures which can influence transcription [55, 56]. Lysine methylation has a different impact on transcription, depending on the positions and degree of methylation (mono-, di-, tri-methylation). Methylation of H3 lysine (H3 K4 and 36) is associated with transcribed domains, whereas methylation of H3 K9, H3 K27 and H4 K20 appears to correlate with transcriptional repression. Human Chd1 binds to methylated H3 K4 through its tandem chromodomains, linking the recognition of histone modifications to non-covalent chromatin remodeling . In contrast, methylated H3 K9 and H3 K27 are recognized by heterochromatin protein 1 (HP1) and polycomb repressive complexes (PRC). Different from histone acetylation, which has been known to be implicated in NER for a long time, histone methylation was found to be implicated in NER recently [58, 59]. The knockdown of the best known methyltransferase of histone H3 K79 (called Dot1 in yeast or DOT1L in mammals), results in complete loss of methylation on this site either in yeast , flies  or mice . In mammaliam cells, several enzymes target histone H4 K20 methylation. Mouse cells lacking the Suv4-20h histone methyltransferase have only mono-methylated but essentially no di- and tri-methylated H4 K20. These mutant mouse cells are sensitive to DNA damaging agents, including UV and defective in repair of DSBs . However, if methylation of histone H4 K20 also plays a role in NER is unknown. Moreover, there is not much knowledge about its role in DNA repair in mammalian cells. Finally, it has not been determined yet if global histone methylation levels change in response to DNA damage, although it is well known that they affect cell cycle checkpoints through interactions with checkpoint components.
4.4. Histone ubiquitination
All of the previously described histone modifications result in relatively small molecular changes in the aminoacid side chains. In contrast, ubiquitination results in a much larger covalent modification. Ubiquitin itself is a 76-amino acid polypeptide that is attached to histone lysines via the sequential action of three enzymes, E1-activating, E2-conjugating and E3-ligating enzymes . Histones H2B, H3 and H4 are constitutively ubiquitinated, but at very low levels (0.3% of the total H3, 0.1% for H4) . In an effort to purify and characterize histone ubiquitin ligases, it was found an ubiquitin ligase activity capable of ubiquitinating all histones
5. ATP-dependent chromatin remodeling during NER
Chromatin remodeling complexes (CRCs) in contrast to PTMs utilize the energy of ATP to disrupt nucleosome DNA contacts, move nucleosomes along DNA and remove or exchange nucleosomes . Thus, they make DNA/chromatin available to proteins that need to access DNA or histones during cellular processes . A large array of different chromatin-remodeling complexes has been identified, which play important roles in controlling gene expression by regulating recruitment and access of transcription factors . ATP-dependent chromatin remodelers belong to the SWI2/SNF2 (switching/sucrose non fermenting) superfamily and can be divided into several subfamilies on the basis of their ATPase domain structure and protein motifs outside the ATPase domain . Among the different complexes identified in different species, four structurally related families have been described: SWI/SNF (switching defective/sucrose non fermenting), INO80 (inositol requiring 80), CHD (chromodomain, helicase, DNA binding) and ISWI (imitation SWI). Each family is defined by its characteristic catalytic ATPase core enzyme from the SWI2/SNF2 . The essential role of these enzymes is reflected in the fact that many of them are required for diverse but specific aspects of embryonic development including pluripotency, cardiac development, dendritic morphogenesis and self-renewal of neural stem cells. However, in adults, deletion or mutation of these proteins often leads to apoptosis or tumorigenesis as a consequence of dysregulated cell cycle control. In recent years, it has become clear that ATP-dependent chromatin remodeling factors not only are involved in transcription regulation, but also play an important role in a number of DNA repair pathways including double strand break repair, base excision repair as well as nucleotide excision repair (NER) . UVC damage itself enhances unwrapping of nucleosomes, which normally exist in a dynamic equilibrium between wrapping and unwrapping . This enhanced “DNA breathing” may assist the repair of lesions in chromatin by increasing the time window for repair factor access and their binding to lesions might further unwrap the DNA . ATP-dependent chromatin remodeling may play a role in opening the chromatin structure for access during DNA damage repair, facilitating the early step of NER in the recognition of the damage . In this respect, three SWI2/SNF2 subfamilies have been implicated in the cell response to UVC radiation as it is shown in Table 1 [71, 77]. Several factors have been implicated on stimulating the repair of UVC-induced DNA damage by increasing chromatin accessibility. Numerous studies showed that there is an association between histone hyperacetylation and chromatin relaxation in response to UVC-irradiation that enhances NER . GCN5-mediated acetylation of histone H3 contribute to the recruitment of the SWI/SNF chromatin remodeling complex via the bromodomains of BRG1 or hBRM . CSB/ERCC6, one of the major TCR proteins, contains a SWI2/SNF2 ATPase domain, which is essential for recruitment of the protein to chromatin . CSB is able to remodel chromatin
|SWI/SNF||BAF||SMARCA4/BRG1, SMARCA2/BRM||Stimulates the removal of 6–4PPs and CPDs in a UVC-dependent histone H3 hyperacetylation manner |
|INO80||INO80||INO80||Promotes the removal of UVC lesions (CPDs,6–4PPs) by NER in not transcribed regions |
|ISWI||ACF||SMARCA5/hSNF2H||Not fully understood |
|OTHER||ERCC6/CSB||Remodels chromatin |
The SWI/SNF chromatin-remodeling complex plays essential roles in a variety of cellular processes including differentiation, proliferation and DNA repair. Loss of SWI/SNF subunits has been reported in a number of malignant cell lines and tumors, and a large number of experimental observations suggest that this complex functions as a tumor suppressor . Interestingly, inactivation of the SWI/SNF-like BRG1/BRM-associated factors (BAF) complexes renders human cells sensitive to DNA damaging agents, such as UVC and ionizing radiation . The mammalian SWI/SNF complexes contain either of two ATPase subunits, BRM (brahma) or BRG1 (Brahma Related Gene). Both of them form a discrete complex by interacting with other BAFs and may have distinct roles in cellular processes [65, 81].
Several studies have indicated that the SWI/SNF complex plays an essential role in the removal of UVC-damage by NER . In mammals, the SWI/SNF ATPase subunit BRG1/SMARCA4 stimulates efficient repair of CPDs but not of 6-4PPs. For Example, BRG1 interacts with XPC and it is recruited to an UVC lesion in a DDB2  and XPC  dependent manner. BRG1, in turn, modulates UVC-induced chromatin remodeling and XPC stability and subsequently promotes damage excision and repair synthesis by facilitating the recruitment of XPG and PCNA to the damage site , suggesting the essential role of Brg1 in prompt elimination of UVC-induced DNA damage by NER in mammalian cells. Finally, BRG1 may also transcriptionally regulate the UVC-induced G1/S checkpoint, as loss of BRG1 leads to increased UVC-induced apoptosis . Besides BRG1, the mammalian SWI/SNF subunit SNF5/SMARCB1 also interacts with XPC. Inactivation of SNF5 causes UVC hypersensitivity and inefficient CPD removal . Intriguingly, BRG1/BRM, but none of the other subunits, is also important to the UVC response in germ cells, suggesting that the involvement of individual SWI/SNF subunits may differ between cell types. Interestingly, UVC hypersensitivity resulting from BRG1 inactivation depends on the presence of the checkpoint protein TP53, extending the complexity of the involvement of BRG1 in UVC-induced DNA damage response . Several lines of evidence suggest that recruitment of factors like SWI/SNF and their functional participation help to recruit downstream factors for processing DNA damage.
The INO80 family of CRCs function in a diverse array of cellular processes, including DNA repair, cell cycle checkpoint and telomeric stability [84, 85]. The INO80 complex also contains three actin-related proteins (ARPs). ARP5 and ARP8 are specific to the INO80 complex. Deletion of either INO80-specific ARP compromises the ATPase activity of the remaining complex and gives rise to DNA-damage-sensitive phenotypes indistinguishable to the INO80 null mutant . Purification of human INO80 revealed a complex with virtually identical core components and a role in transcription [87, 88], indicating that the INO80 complex is highly conserved within eukaryotes . The role for various remodeling activities is likely to promote the timely repair of lesions, rather than being an essential component for lesion removal. For example, some observations suggest that loss of remodeling activity leads to attenuation of photolesion repair, but not a complete impairment. Thus, it supports the idea that INO80 carry out an important chromatin remodeling activity for an efficient NER . The link between INO80 and NER function may reflect the underlying mechanism for the UVC hypersensitivity of INO80 mutant cells and the broadening connections between chromatin remodeling and DNA repair in general . The mammalian INO80 complex functions during earlier NER steps facilitating the recruitment of early NER factors such as XPC and XPA and, in contrast to yeast, it localizes to DNA damage independently of XPC . Furthermore, INO80 facilitates efficient 6-4PPs and CPDs removal and together with the Arp5/ ACTR5 subunit, interacts with the NER initiation factor DDB1, but not with XPC. These discrepancies may reflect interspecies differences, but may also point out multiple functions of INO80 chromatin remodeling during NER that are experimentally difficult to dissect. INO80 may function to facilitate damage detection as well as to restore chromatin after damage has been repaired . A recent study shows that the INO80 complex plays an important role in facilitating NER by providing access to lesion processing factors, suggesting a functional connection between INO80-dependent chromatin remodeling and NER .
ISWI complexes are a second major category of ATP-dependent chromatin remodeling complexes. In mammals, two ISWI-homologs, named SNF2H and SNF2L, have been described. While most of the complexes contain SNFH; up to now, SNF2L has only been found in the human NURF complex [90, 91]. Subunits related to ACF1 are similar to these ISWI-containing remodeling complexes, which contain PHD and bromodomains . Snf2h is a gene essential for the early development of mammalian embryos, suggesting that ISWI complexes  may be required for cell proliferation . Besides, ISWI cooperates with histone chaperones in the assembly and remodeling of chromatin . These complexes accumulate at sites of heterochromatin concomitant with their replication, suggesting a role for ISWI chromatin remodeling functions in replication of DNA in highly condensed chromatin . ISWI complexes also may have a role in facilitating repair and recombination of DNA in chromatin. Several experiments have suggested that ISWI-mediated chromatin remodeling also functions to regulate NER, although its precise role remains unknown . Moreover, SNF2H interacts with CSB , and the ACF1 subunit is recruited to UVC-induced DNA damage . Knockdown of the mammalian ISWI ATPase SNF2H/SMARCA5 or its auxiliary factor ACF1/BAZ1A also leads to mild UVC sensitivity . However, further experimental evidence is required to understand how ISWI chromatin remodeling functions in the UVC-DNA damage response.
6. Discussion and perspectives
When DNA is damaged, the chromatin, far from acting as an inhibitory barrier to lesion removal, can actively signal its presence, promoting the overall physiological response of the cell to damage, which stimulates the removal of the DNA damage itself. By the same token, the most challenging step in NER is the recognition of DNA lesions in their chromatin context. Nucleosomes on damaged DNA inhibit efficient NER and a functional connection between chromatin remodeling and the initiation steps of NER has been described .
In this respect, the relevance of the histone acetylation balance and some ATP-dependent chromatin remodeling complexes to facilitate the early damage-recognition step of NER has been demonstrated, since changes in chromatin conformation could interfere with the correct interactions between repair proteins and DNA lesions which are immersed in a dynamic chromatin structure [38, 76, 100]. Besides, neuronal survival has been related to the balance between HAT and HDAC activities . For example, it has been shown that in the presence of histone deacetylase inhibitors, normal neuron cells increase the frequency of apoptosis. Moreover, in transgenic mice, carrying neurodegeneration diseases characterized by histone hypoacetylation, their neurodegeneration phenotypes can be diminished in the presence of HDAC inhibitors [102, 103]. By the same token, alterations in the acetylation/deacetylation balance by changes in HATs or HDACs activities have been associated with the development of different cancers .
Another interesting issue in favor of the relevance of chromatin remodeling is the fact that transcription coupled repair (TCR) seems not to be responsible for the higher UVC sensitivity evidenced through the increased frequency of chromosomal aberrations observed in Cockayne’s Syndrome (CS) simile cells exposed to UVC . In this respect, we have found that chromosome breakpoints were distributed more random in CS simile cells than in normal ones instead of being concentrated on the transcribed chromosome regions as expected . Since DNA accessibility for DNA repair proteins is limited in nucleosomes [16, 75], different chromatin organization after UVC exposure in CS simile cells could influence the distribution of CPDs in eu- and heterochromatic regions as well as their removal by TCR, leading to increased frequencies of chromosomal aberrations in these cells.
Although many of the chromatin remodeling factors observed in yeast have also been found in mammals, different functions have been attributed to some of them (i.e. H3K56 acetylation and INO80 mentioned previously), indicating that in spite of being quite well evolutionary conserved, they could have another function in mammals. Moreover, due to the multifunctional role of chromatin remodeling complexes become still very difficult to arise questions such as by which mechanism the damage is sensed or how the cell is able to choose a particular repair pathway, by which mechanisms chromatin remodelers are directed to a specific repair pathway or by which mechanisms chromatin reassembly takes place. Therefore, it is clear that we just begin to understand the DNA repair in the context of chromatin and, therefore, further work it is needed to elucidate either the individual functions or the coordinated activities of chromatin remodeling in all DNA repair pathways.
Abbreviations and acronyms
|6-4PP||Pyrimidine 6-4 pyrimidone photoproducts|
|ASF1A||Histone chaperone anti-silencing function1A|
|ATM||Ataxia telangiectasia mutated|
|ATRIP||ATR interacting protein|
|BRG1||Brahma Related Gene|
|CAF-1||Chromatin assembly factor 1|
|CPDs||Cyclobutane pyrimidine dimers|
|CRCs||Chromatin remodeling complexes|
|CSB||Cockayne syndrome group B protein|
|CUL4–DDB–ROC1||Culin 4- DNA damage-binding protein- RING finger protein|
|CHO||Chinese hamster cell lines|
|ERCC1||Excision repair cross complementing 1|
|ERCC6||Excision repair cross complementing 6|
|GCN5||General control non-derepressible 5|
|GGR||Global genome repair|
|hHR23B||Human homologue of the yeast protein RAD23|
|HMGB1||High mobility group protein B1|
|HP1||Heterochromatin protein 1|
|ING||Inhibitor of growth|
|INO80||Inositol requiring 80|
|MBT||Malignant brain tumor|
|NER||Nucleotide excision repair|
|NURF||Nucleosome remodeling factor|
|p300||Histone acetyltransferase named p300|
|p53||Tumor supressor p53 gene|
|PCNA||Proliferating cell nuclear antigen|
|PHD||Plant Homeo Domain|
|PTMs||Histone post-translational modifications|
|RNF8||Ring finger protein 8|
|RPA||Replication protein A|
|SMARCA4||Transcription activator BRG1|
|SNF2H and SNF2L||ISWI-homologs|
|SNF5/SMARCB1||Mammalian SWI/SNF subunit|
|SSBs||Single strand breaks|
|STAGA||SAGA-like complex containing GCN5L|
|SWI/SNF||Switching defective/sucrose non fermenting|
|SWI2/SNF2||Switching/sucrose non fermenting|
|TCR||Transcriptional coupled repair|
|TFIIH||Transcription factor II H|
|TP53||Tumor suppressor protein 53|
|UVC||Ultraviolet light C|
|UV-DDB||UV-damaged DNA binding protein consisting of two subunits (DDB1 and DDB2)|
|XPA||Xeroderma Pigmentosum group A|
|XPB||Xeroderma Pigmentosum group B|
|XPC||Xeroderma Pigmentosum group C|
|XPD||Xeroderma Pigmentosum group D|
|XPE||Xeroderma Pigmentosum group E|
|XPF||Xeroderma Pigmentosum group F|
|XPG||Xeroderma Pigmentosum group G|
AcknowledgmentsThis work was partially supported by the Program of Development of the Basic Sciences (PEDECIBA) from Uruguay. W M-L was supported by a Marie Curie Fellowship from the Frame Program Seven (EC-FP7) of the European Community. L M-A was supported by a Post-graduate fellowship of the National Agency of Research and Innovation (ANII) from Uruguay.
Nag R, Smerdon MJ. Altering the chromatin landscape for nucleotide excision repair. Mutation research2009; 682(1):13-20.
Strahl BD, Allis CD. The language of covalent histone modifications. Nature2000; 403(6765):41-45.
Hassa PO, Hottiger MO. An epigenetic code for DNA damage repair pathways? Biochemistry and cell biology2005; 83(3):270-285.
Loizou JI, Murr R, Finkbeiner MG, Sawan C, Wang ZQ, Herceg Z. Epigenetic information in chromatin: the code of entry for DNA repair. Cell Cycle2006; 5(7):696-701.
Lans H, Marteijn JA, Vermeulen W. ATP-dependent chromatin remodeling in the DNA-damage response. Epigenetics & chromatin2012; 5:4.
Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell research2011; 21(3):381-395.
Ataian Y, Krebs JE. Five repair pathways in one context: chromatin modification during DNA repair. Biochemistry and cell biology2006; 84(4):490-494.
Green CM, Almouzni G. Local action of the chromatin assembly factor CAF-1 at sites of nucleotide excision repair in vivo. The EMBO journal2003; 22(19):5163-5174.
Karagiannis TC, El-Osta A. Chromatin modifications and DNA double-strand breaks: the current state of play. Leukemia2007; 21(2):195-200.
Escargueil AE, Soares DG, Salvador M, Larsen AK, Henriques JA. What histone code for DNA repair? Mutation research2008; 658(3):259-270.
Méndez-Acuña L, Di Tomaso M, Palitti F, Martínez-López W. Histone post-translational modifications in DNA damage response. Cytogenetic and genome research2010; 128(1-3):28-36.
Tjeertes JV, Miller KM, Jackson SP. Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. The EMBO journal2009; 28(13):1878-1889.
Farrell AW, Halliday GM, Lyons JG. Chromatin Structure Following UV-Induced DNA Damage-Repair or Death? Int J Mol Sci2011; 12(11):8063-8085.
Duan MR, Smerdon MJ. UV damage in DNA promotes nucleosome unwrapping. J Biol Chem2010; 285(34):26295-26303.
Korolev V. Chromatin and DNA damage repair. Russian Journal of Genetics2011; 47(4):394-403.
Thoma F. Light and dark in chromatin repair: repair of UV-induced DNA lesions by photolyase and nucleotide excision repair. EMBO J1999; 18(23):6585-6598.
Hara R, Mo J, Sancar A. DNA damage in the nucleosome core is refractory to repair by human excision nuclease. Mol Cell Biol2000; 20(24):9173-9181.
Ura K, Araki M, Saeki H, Masutani C, Ito T, Iwai S, Mizukoshi T, Kaneda Y, Hanaoka F. ATP-dependent chromatin remodeling facilitates nucleotide excision repair of UV-induced DNA lesions in synthetic dinucleosomes. EMBO J2001; 20(8):2004-2014.
Allis CD. Epigenetics. Cold Spring Harbor, N. Y.: CSHL Press; 2007.
Gong F, Kwon Y, Smerdon MJ. Nucleotide excision repair in chromatin and the right of entry. DNA Repair (Amst)2005; 4(8):884-896.
Reed SH. Nucleotide excision repair in chromatin: damage removal at the drop of a HAT. DNA Repair (Amst)2011; 10(7):734-742.
Green CM, Almouzni G. When repair meets chromatin. First in series on chromatin dynamics. EMBO reports2002; 3(1):28-33.
Ura K, Hayes JJ. Nucleotide excision repair and chromatin remodeling. Eur J Biochem2002; 269(9):2288-2293.
Gong F, Fahy D, Smerdon MJ. Rad4-Rad23 interaction with SWI/SNF links ATP-dependent chromatin remodeling with nucleotide excision repair. Nat Struct Mol Biol2006; 13(10):902-907.
Dinant C, Houtsmuller AB, Vermeulen W. Chromatin structure and DNA damage repair. Epigenetics & chromatin2008; 1(1):9.
de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis2000; 21(3):453-460.
Nouspikel T. DNA repair in mammalian cells : Nucleotide excision repair: variations on versatility. Cellular and molecular life sciences : CMLS2009; 66(6):994-1009.
Mitchell JR, Hoeijmakers JH, Niedernhofer LJ. Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr Opin Cell Biol2003; 15(2):232-240.
Volker M, Moné MJ, Karmakar P, van Hoffen A, Schul W, Vermeulen W, Hoeijmakers JHJ, van Driel R, van Zeeland AA, Mullenders LHF. Sequential assembly of the nucleotide excision repair factors in vivo. Molecular cell2001; 8(1):213-224.
Giglia-Mari G, Zotter A, Vermeulen W. DNA damage response. Cold Spring Harb Perspect Biol2011; 3(1):a000745.
Zhu Q, Wani G, Arab HH, El-Mahdy MA, Ray A, Wani AA. Chromatin restoration following nucleotide excision repair involves the incorporation of ubiquitinated H2A at damaged genomic sites. DNA repair2009; 8(2):262-273.
Cleaver JE, Lam ET, Revet I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nature Reviews Genetics2009; 10(11):756-768.
Moné MJ, Bernas T, Dinant C, Goedvree FA, Manders EMM, Volker M, Houtsmuller AB, Hoeijmakers JHJ, Vermeulen W, Van Driel R. In vivo dynamics of chromatin-associated complex formation in mammalian nucleotide excision repair. Proceedings of the National Academy of Sciences of the United States of America2004; 101(45):15933.
Rubbi CP, Milner J. p53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage. EMBO J2003; 22(4):975-986.
Polo SE, Roche D, Almouzni G. New histone incorporation marks sites of UV repair in human cells. Cell2006; 127(3):481-493.
Ramanathan B, Smerdon MJ. Enhanced DNA repair synthesis in hyperacetylated nucleosomes. The Journal of biological chemistry1989; 264(19):11026-11034.
Yu Y, Teng Y, Liu H, Reed SH, Waters R. UV irradiation stimulates histone acetylation and chromatin remodeling at a repressed yeast locus. Proc Natl Acad Sci U S A2005; 102(24):8650-8655.
Guo R, Chen J, Mitchell DL, Johnson DG. GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damage. Nucleic Acids Res2011; 39(4):1390-1397.
Datta A, Bagchi S, Nag A, Shiyanov P, Adami GR, Yoon T, Raychaudhuri P. The p48 subunit of the damaged-DNA binding protein DDB associates with the CBP/p300 family of histone acetyltransferase. Mutation Research/DNA Repair2001; 486(2):89-97.
Martinez E, Palhan VB, Tjernberg A, Lymar ES, Gamper AM, Kundu TK, Chait BT, Roeder RG. Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. Molecular and cellular biology2001; 21(20):6782-6795.
Wang J, Chin MY, Li G. The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation. Cancer research2006; 66(4):1906-1911.
Fousteri M, Vermeulen W, van Zeeland AA, Mullenders LH. Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo. Mol Cell2006; 23(4):471-482.
Martínez-López W, Folle G, Obe G, Jeppesen P. Chromosome regions enriched in hyperacetylated histone H4 are preferred sites for endonuclease-and radiation-induced breakpoints. Chromosome Research2001; 9(1):69-75.
Martínez-López W, Di Tomaso M. Chromatin remodelling and chromosome damage distribution. Human & experimental toxicology2006; 25(9):539-545.
Battu A, Ray A, Wani AA. ASF1A and ATM regulate H3K56-mediated cell-cycle checkpoint recovery in response to UV irradiation. Nucleic Acids Research2011; 39(18):7931-7945.
Nightingale K, Dimitrov S, Reeves R, Wolffe AP. Evidence for a shared structural role for HMG1 and linker histones B4 and H1 in organizing chromatin. The EMBO journal1996; 15(3):548-561.
Bonaldi T, Längst G, Strohner R, Becker PB, Bianchi ME. The DNA chaperone HMGB1 facilitates ACF/CHRAC-dependent nucleosome sliding. The EMBO journal2002; 21(24):6865-6873.
Lange SS, Mitchell DL, Vasquez KM. High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage. Proceedings of the National Academy of Sciences of the United States of America2008; 105(30):10320-10325.
Reddy MC, Christensen J, Vasquez KM. Interplay between human high mobility group protein 1 and replication protein A on psoralen-cross-linked DNA. Biochemistry2005; 44(11):4188-4195.
Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell2012; 150(1):12-27.
Jeggo P, Lobrich M. Radiation-induced DNA damage responses. Radiation protection dosimetry2006; 122(1-4):124-127.
Hanasoge S, Ljungman M. H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase. Carcinogenesis2007; 28(11):2298-2304.
Marti TM, Hefner E, Feeney L, Natale V, Cleaver JE. H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks. Proc Natl Acad Sci U S A2006; 103(26):9891-9896.
Moore JD, Yazgan O, Ataian Y, Krebs JE. Diverse roles for histone H2A modifications in DNA damage response pathways in yeast. Genetics2007; 176(1):15-25.
Kouzarides T. Chromatin modifications and their function. Cell2007; 128(4):693-705.
Ehrenhofer-Murray AE. Chromatin dynamics at DNA replication, transcription and repair. Eur J Biochem2004; 271(12):2335-2349.
Sims III RJ, Chen CF, Santos-Rosa H, Kouzarides T, Patel SS, Reinberg D. Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains. Journal of Biological Chemistry2005; 280(51):41789-41792.
Nguyen AT, Zhang Y. The diverse functions of Dot1 and H3K79 methylation. Genes & development2011; 25(13):1345-1358.
Li S. Implication of Posttranslational Histone Modifications in Nucleotide Excision Repair. International Journal of Molecular Sciences2012; 13(10):12461-12486.
van Leeuwen F, Gafken PR, Gottschling DE. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell2002; 109(6):745-756.
Shanower GA, Muller M, Blanton JL, Honti V, Gyurkovics H, Schedl P. Characterization of the grappa gene, the Drosophila histone H3 lysine 79 methyltransferase. Genetics2005; 169(1):173-184.
Jones B, Su H, Bhat A, Lei H, Bajko J, Hevi S, Baltus GA, Kadam S, Zhai H, Valdez R et al. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS genetics2008; 4(9):e1000190.
Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E, Celeste A, Pagani M, Opravil S, De La Rosa-Velazquez IA et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes & development2008; 22(15):2048-2061.
Nouspikel T. Multiple roles of ubiquitination in the control of nucleotide excision repair. Mechanisms of ageing and development2011; 132(8-9):355-365.
Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell2006; 22(3):383-394.
Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G, Mori T, Iwai S, Tanaka K, Hanaoka F. UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell2005; 121(3):387-400.
El-Mahdy MA, Zhu Q, Wang QE, Wani G, Praetorius-Ibba M, Wani AA. Cullin 4A-mediated proteolysis of DDB2 protein at DNA damage sites regulates in vivo lesion recognition by XPC. The Journal of biological chemistry2006; 281(19):13404-13411.
Takedachi A, Saijo M, Tanaka K. DDB2 complex-mediated ubiquitylation around DNA damage is oppositely regulated by XPC and Ku and contributes to the recruitment of XPA. Molecular and cellular biology2010; 30(11):2708-2723.
Marteijn JA, Bekker-Jensen S, Mailand N, Lans H, Schwertman P, Gourdin AM, Dantuma NP, Lukas J, Vermeulen W. Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. The Journal of cell biology2009; 186(6):835-847.
Lan L, Nakajima S, Kapetanaki MG, Hsieh CL, Fagerburg M, Thickman K, Rodriguez-Collazo P, Leuba SH, Levine AS, Rapic-Otrin V. Monoubiquitinated histone H2A destabilizes photolesion-containing nucleosomes with concomitant release of UV-damaged DNA-binding protein E3 ligase. The Journal of biological chemistry2012; 287(15):12036-12049.
Hargreaves DC, Crabtree GR. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell research2011; 21(3):396-420.
Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem2009; 78:273-304.
Bell O, Tiwari VK, Thoma NH, Schubeler D. Determinants and dynamics of genome accessibility. Nature reviews Genetics2011; 12(8):554-564.
Udugama M, Sabri A, Bartholomew B. The INO80 ATP-dependent chromatin remodeling complex is a nucleosome spacing factor. Mol Cell Biol2011; 31(4):662-673.
Thoma F. Repair of UV lesions in nucleosomes--intrinsic properties and remodeling. DNA Repair (Amst)2005; 4(8):855-869.
Zhao Q, Wang QE, Ray A, Wani G, Han C, Milum K, Wani AA. Modulation of nucleotide excision repair by mammalian SWI/SNF chromatin-remodeling complex. J Biol Chem2009; 284(44):30424-30432.
Vignali M, Hassan AH, Neely KE, Workman JL. ATP-dependent chromatin-remodeling complexes. Mol Cell Biol2000; 20(6):1899-1910.
Lake RJ, Geyko A, Hemashettar G, Zhao Y, Fan HY. UV-induced association of the CSB remodeling protein with chromatin requires ATP-dependent relief of N-terminal autorepression. Molecular cell2010; 37(2):235-246.
Citterio E, Van Den Boom V, Schnitzler G, Kanaar R, Bonte E, Kingston RE, Hoeijmakers JH, Vermeulen W. ATP-dependent chromatin remodeling by the Cockayne syndrome B DNA repair-transcription-coupling factor. Mol Cell Biol2000; 20(20):7643-7653.
Reisman D, Glaros S, Thompson E. The SWI/SNF complex and cancer. Oncogene2009; 28(14):1653-1668.
Gong F, Fahy D, Liu H, Wang W, Smerdon MJ. Role of the mammalian SWI/SNF chromatin remodeling complex in the cellular response to UV damage. Cell Cycle2008; 7(8):1067-1074.
Ray A, Mir SN, Wani G, Zhao Q, Battu A, Zhu Q, Wang QE, Wani AA. Human SNF5/INI1, a component of the human SWI/SNF chromatin remodeling complex, promotes nucleotide excision repair by influencing ATM recruitment and downstream H2AX phosphorylation. Mol Cell Biol2009; 29(23):6206-6219.
Zhang L, Zhang Q, Jones K, Patel M, Gong F. The chromatin remodeling factor BRG1 stimulates nucleotide excision repair by facilitating recruitment of XPC to sites of DNA damage. Cell Cycle2009; 8(23):3953-3959.
Vincent JA, Kwong TJ, Tsukiyama T. ATP-dependent chromatin remodeling shapes the DNA replication landscape. Nat Struct Mol Biol2008; 15(5):477-484.
Pisano S, Leoni D, Galati A, Rhodes D, Savino M, Cacchione S. The human telomeric protein hTRF1 induces telomere-specific nucleosome mobility. Nucleic Acids Research2010; 38(7):2247-2255.
Shen X, Ranallo R, Choi E, Wu C. Involvement of actin-related proteins in ATP-dependent chromatin remodeling. Molecular cell2003; 12(1):147-155.
Cai Y, Jin J, Yao T, Gottschalk AJ, Swanson SK, Wu S, Shi Y, Washburn MP, Florens L, Conaway RC. YY1 functions with INO80 to activate transcription. Nature structural & molecular biology2007; 14(9):872-874.
Jin J, Cai Y, Yao T, Gottschalk AJ, Florens L, Swanson SK, Gutiérrez JL, Coleman MK, Workman JL, Mushegian A. A mammalian chromatin remodeling complex with similarities to the yeast INO80 complex. Journal of Biological Chemistry2005; 280(50):41207-41212.
Jiang Y, Wang X, Bao S, Guo R, Johnson DG, Shen X, Li L. INO80 chromatin remodeling complex promotes the removal of UV lesions by the nucleotide excision repair pathway. Proceedings of the National Academy of Sciences2010; 107(40):17274-17279.
Barak O, Lazzaro MA, Lane WS, Speicher DW, Picketts DJ, Shiekhattar R. Isolation of human NURF: a regulator of Engrailed gene expression. The EMBO journal2003; 22(22):6089-6100.
Bozhenok L, Wade PA, Varga-Weisz P. WSTF–ISWI chromatin remodeling complex targets heterochromatic replication foci. The EMBO journal2002; 21(9):2231-2241.
Längst G, Becker PB. Nucleosome mobilization and positioning by ISWI-containing chromatin-remodeling factors. Journal of cell science2001; 114(14):2561.
Strohner R, Nemeth A, Jansa P, Hofmann-Rohrer U, Santoro R, Längst G, Grummt I. NoRC—a novel member of mammalian ISWI-containing chromatin remodeling machines. The EMBO journal2001; 20(17):4892-4900.
Stopka T, Skoultchi AI. The ISWI ATPase Snf2h is required for early mouse development. Proceedings of the National Academy of Sciences of the United States of America2003; 100(24):14097.
Emelyanov AV, Vershilova E, Ignatyeva MA, Pokrovsky DK, Lu X, Konev AY, Fyodorov DV. Identification and characterization of ToRC, a novel ISWI-containing ATP-dependent chromatin assembly complex. Genes & development2012; 26(6):603-614.
Eberharter A, Becker PB. ATP-dependent nucleosome remodelling: factors and functions. J Cell Sci2004; 117(Pt 17):3707-3711.
Cavellan E, Asp P, Percipalle P, Farrants AK. The WSTF-SNF2h chromatin remodeling complex interacts with several nuclear proteins in transcription. J Biol Chem2006; 281(24):16264-16271.
Luijsterburg MS, Dinant C, Lans H, Stap J, Wiernasz E, Lagerwerf S, Warmerdam DO, Lindh M, Brink MC, Dobrucki JW et al. Heterochromatin protein 1 is recruited to various types of DNA damage. The Journal of cell biology2009; 185(4):577-586.
Sanchez-Molina S, Mortusewicz O, Bieber B, Auer S, Eckey M, Leonhardt H, Friedl AA, Becker PB. Role for hACF1 in the G2/M damage checkpoint. Nucleic Acids Res2011; 39(19):8445-8456.
Fousteri M, Mullenders LH. Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. Cell research2008; 18(1):73-84.
Rouaux C, Loeffler JP, Boutillier AL. Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. Biochemical pharmacology2004; 68(6):1157-1164.
Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Sobue G. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Human molecular genetics2004; 13(11):1183-1192.
Ryu H, Smith K, Camelo SI, Carreras I, Lee J, Iglesias AH, Dangond F, Cormier KA, Cudkowicz ME, H Brown Jr R. Sodium phenylbutyrate prolongs survival and regulates expression of anti‐apoptotic genes in transgenic amyotrophic lateral sclerosis mice. Journal of neurochemistry2005; 93(5):1087-1098.
Lafon-Hughes L, Di Tomaso MV, Méndez-Acuña L, Martínez-López W. Chromatin-remodelling mechanisms in cancer. Mutation Research/Reviews in Mutation Research2008; 658(3):191-214.
De Santis LP, Garcia CL, Balajee AS, Brea Calvo GT, Bassi L, Palitti F. Transcription coupled repair deficiency results in increased chromosomal aberrations and apoptotic death in the UV61 cell line, the Chinese hamster homologue of Cockayne's syndrome B. Mutation Research/DNA Repair2001; 485(2):121-132.
Martínez-López W, Marotta E, Di Tomaso M, Méndez-Acuña L, Palitti F. Distribution of UVC-induced chromosome aberrations along the X chromosome of TCR deficient and proficient Chinese hamster cell lines. Mutation Research/Genetic Toxicology and Environmental Mutagenesis2010; 701(1):98-102.