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ATP-dependent chromatin remodeling in the DNA-damage response

Hannes Lans, Jurgen A Marteijn, Wim Vermeulen

Epigenetics & Chromatin · 2012 · Review

Abstract

The integrity of DNA is continuously challenged by metabolism-derived and environmental genotoxic agents that cause a variety of DNA lesions, including base alterations and breaks. DNA damage interferes with vital processes such as transcription and replication, and if not repaired properly, can ultimately lead to premature aging and cancer. Multiple DNA pathways signaling for DNA repair and DNA damage collectively safeguard the integrity of DNA. Chromatin plays a pivotal role in regulating DNA-associated processes, and is itself subject to regulation by the DNA-damage response. Chromatin influences access to DNA, and often serves as a docking or signaling site for repair and signaling proteins. Its structure can be adapted by post-translational histone modifications and nucleosome remodeling, catalyzed by the activity of ATP-dependent chromatin-remodeling complexes. In recent years, accumulating evidence has suggested that ATP-dependent chromatin-remodeling complexes play important, although poorly characterized, roles in facilitating the effectiveness of the DNA-damage response. In this review, we summarize the current knowledge on the involvement of ATP-dependent chromatin remodeling in three major DNA repair pathways: nucleotide excision repair, homologous recombination, and non-homologous end-joining. This shows that a surprisingly large number of different remodeling complexes display pleiotropic functions during different stages of the DNA-damage response. Moreover, several complexes seem to have multiple functions, and are implicated in various mechanistically distinct repair pathways.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

DNA-damage response

1All living organisms depend on faithful preservation and transmission of genetic information to the next generation. Genetic information is stored within DNA, which is embedded in a dynamic nucleoprotein complex, called chromatin. The integrity of DNA is inescapably and continuously threatened by spontaneous and induced alterations to its basic structure. DNA itself is unstable and undergoes hydrolysis, which creates abasic sites and causes deamination. Furthermore, cellular metabolic processes such as oxidative respiration produce oxygen radicals and other reactive molecules, which damage DNA. Finally, exposure to environmental sources such as solar UV irradiation, × radiation, and numerous chemicals induces DNA injuries.

2DNA damage interferes with vital processes such as transcription and replication, which may cause cells to die or senesce, thus contributing to aging. Replication of damaged DNA templates severely affects the fidelity of the polymerases, and may result in permanent mutations or chromosomal aberrations, which are at the basis of malignant transformation. Genetic erosion and its consequences are neutralized by a variety of DNA repair and associated DNA-damage signaling pathways, collectively called the DNA-damage response (DDR). In this review, we will focus on three repair pathways which are among the best characterized with regard to their repair mechanisms and interactions with chromatin: nucleotide excision repair (NER), which removes helix-distorting intra-strand lesions, and homologous recombination (HR) and non-homologous end-joining (NHEJ), both of which repair double-strand breaks (DSBs).

Chromatin and the DNA-damage response

3All DNA-associated processes, such as transcription, replication, recombination, and DNA repair, are for a large part regulated by the chromatin structure. Because this nucleoprotein complex limits the ability of other proteins to interact with DNA, the chromatin structure needs to be modified to facilitate efficient access to DNA. In addition, DNA processing itself may also lead to changes in the chromatin structure and composition, such as DNA repair-associated post-translational histone modification and exchange. Based on the changes in chromatin observed after NER, it was suggested that chromatin needs to be made more accessible in order to allow efficient damage detection and repair to take place, after which the chromatin structure is restored to prevent genomic instability and possibly to preserve epigenetic information or to leave an imprint of the damage on the chromatin. Particularly for the latter step, clear evidence is available that nucleosome occupancy of repaired DNA is restored by the action of histone chaperones. However, evidence for chromatin remodeling before or during repair seems to be more ambiguous, and difficult to include in a single overarching model.

4Modification of chromatin basically occurs via two mechanisms. First, chromatin can be changed by post-translational modification of histones through the action of histone-modifying enzymes. Second, chromatin can be altered by displacement of histones or entire nucleosomes through the action of ATP-dependent chromatin-remodeling complexes and histone chaperones. Although both mechanisms are interconnected, in this review we will mainly discuss the second mechanism and focus on mammalian cells, although current knowledge in yeast will also be described. Readers interested in DDR-associated post-translational histone modifications are referred to other recent reviews on the subject.

ATP-dependent chromatin-remodeling complexes

5A large array of different chromatin-remodeling complexes has been identified, and these play important roles in controlling gene expression by regulating recruitment and access of transcription factors. In recent years, it has become clear that ATP-dependent chromatin-remodeling complexes also play important roles in the DDR. Using the energy of ATP hydrolysis, these complexes catalyze disruption of DNA-histone contacts, and can slide or evict nucleosomes or alter their composition. Among the different complexes identified in different species, four structurally related families have been described: SWI/SNF (switching defective/sucrose nonfermenting), INO80 (inositol requiring 80), CHD (chromodomain, helicase, DNA binding) and ISWI (imitation switch) (Table 1). Each family is defined by its characteristic catalytic core ATPase enzyme from the SWI2/SNF2 superfamily. ATP-dependent chromatin-remodeling complexes have diverse but specific functions in processes involving DNA metabolism. Although some redundancy occurs, most remodelers are essential for cellular growth, development, or differentiation. Consequently, they have been implicated in many embryonic developmental processes and in tumorigenesis.

Chromatin and nucleotide excision repair

6NER removes a wide range of bulky DNA adducts that distort the double helix, including those induced by UV light. NER is initiated by two damage-recognition pathways, transcription-coupled (TC)-NER and global genome (GG)-NER, which remove damage in roughly four successive steps: 1) lesion detection, 2) local unwinding and damage verification, 3) excision of the DNA surrounding the lesion, and finally 4) DNA synthesis and ligation to fill the resulting gap (Figure 1). Damage that occurs in the transcribed strand of active genes is mainly repaired by TC-NER, whereas damage in non-transcribed DNA is repaired by GG-NER.

7The importance of chromatin remodeling for NER is apparent from many experiments that have shown that NER is more efficient in naked DNA than in chromatin, and 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, the chromatin needs to be adapted. Conversely, DNA injuries may differentially affect chromatin structure. Although NER removes a large variety of structurally unrelated DNA lesions, including UV-induced cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (64PPs), removal efficiency of these lesions differs significantly. For example, in non-transcribed DNA, GG-NER of 64PPs is much faster than GG-NER of CPDs. Chromatin may exert substantial influence on this lesion-specific repair, as 64PPs seem to be predominantly formed in internucleosomal regions, whereas CPDs are formed equally in nucleosomal and internucleosomal DNA. Nevertheless, in naked DNA and nucleosomes, 64PPs are also repaired faster than CPDs. Lesion-specific differences in NER efficiency have also been explained by the degree to which they distort the helical DNA structure and define the affinity for the GG-NER initiation factor XPC. Furthermore, repair of CPDs in non-transcribed DNA depends on the presence of the GG-NER-specific DNA damage-binding (DDB) recognition complex, which is thought to modify chromatin to facilitate binding of XPC. In TC-NER, which is initiated upon stalling of RNA polymerase 2 after damage, different lesions are removed with equal speed. This suggests that differences in repair rate are caused not only by the helix-distorting capacity and chromatin environment, but also by the manner in which lesions are detected. Lesion removal in transcribed DNA occurs more rapidly than in non-transcribed DNA, possibly because both GG-NER and TC-NER remove these lesions, but possibly also because chromatin has already been made more accessible by the transcription machinery.

ATP-dependent chromatin remodeling during nucleotide excision repair

8UV 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 binding of these repair proteins to lesions might further unwrap the DNA. Additionally, access to DNA is likely to be actively induced by multiple ATP-dependent chromatin-remodeling complexes, which have been implicated in the response of cells to UV irradiation (Table 1). One of the major TC-NER proteins, CSB/ERCC6, contains a SWI2/SNF2 ATPase domain, which is essential for recruitment of the protein to chromatin and to its function in repair. CSB is able to remodel chromatin in vitro in an ATP-dependent fashion, and is required for the recruitment of NER factors to sites of TC-NER, but its precise activity and whether it remodels nucleosomes during TC-NER in vivo remains unknown. Another NER factor, Rad16, which is essential for GG-NER in yeast, also contains a SWI2/SNF2 domain. Although Rad16 does not slide or evict nucleosomes, it affects chromatin structure through its DNA translocase activity and by controlling UV-induced histone H3 acetylation induced by the histone acetyltransferase Gcn5.

SWI/SNF

9Accumulating evidence suggests that chromatin is remodeled by SWI/SNF complexes during NER, leading to chromatin relaxation and increased access to DNA of NER initiation factors. In vitro, NER-mediated excision of acetylaminofluorene-guanoside or 64PP lesions within nucleosomal templates is stimulated by purified yeast SWI/SNF. In yeast, the NER initiation complex Rad4-Rad23, orthologous to mammalian XPC/RAD23B, interacts with Snf5 and Snf6, two SWI/SNF complex subunits, in a UV-specific manner. Furthermore, Snf6 and the ATPase Swi2 are required for UV-induced increase in chromatin accessibility, which is also associated with hyperacetylation of histones H3 and H4. Likewise, in mammals, the SWI/SNF ATPase BRG1/SMARCA4 stimulates efficient repair of CPDs but not of 64PPs, and associates with the recognition factors DDB2 and XPC. However, conflicting results have been reported about whether BRG1 stimulates recruitment of XPC to sites of DNA damage or, vice versa, whether XPC stimulates BRG1 recruitment, which in turn stimulates recruitment of later NER factors. Finally, BRG1 may also transcriptionally regulate the UV-induced G1/S checkpoint, as loss of BRG1 leads to increased UV-induced apoptosis.

10Besides BRG1, the mammalian SWI/SNF subunit SNF5/SMARCB1 also interacts with XPC. Inactivation of SNF5 causes UV hypersensitivity and inefficient CPD repair, although this has been challenged by a study in which no effect of SNF5 depletion on UV sensitivity was found. These differences may be due to the use of different assays and cells. In a genetic screen, our laboratory identified different subunits of SWI/SNF complexes, including orthologs of mammalian BRG1 and BRM/SMARCA2, SNF5, PBRM1 and BAF155/SMARCC1, which are essential for optimal UV survival of somatic cells in Caenorhabditis elegans. Intriguingly, BRG1/BRM, but none of the other subunits, is also important to the UV response of germ cells, suggesting that the involvement of individual SWI/SNF subunits may differ between cell types. Importantly, UV hypersensitivity resulting from BRG1 inactivation depends on the presence of the checkpoint protein TP53, extending the complexity of the involvement of BRG1 in UV-induced DDR. How exactly SWI/SNF remodelers impinge on NER is as yet unknown, but the available data support a regulatory role in the damage-detection step of NER (Figure 2).

INO80

11The INO80 chromatin-remodeling complex probably also remodels chromatin during NER (Figure 2). Both yeast ino80 mutants and mammalian INO80-deficient cells are sensitive to UV irradiation. Yeast Ino80 interacts with Rad4 and Rad23, and is recruited to damaged chromatin in a Rad4-dependent manner, where it is required for restoration of repair-induced nucleosome loss. Whether yeast Ino80 is also involved in earlier repair events is controversial. The mammalian INO80 complex functions during earlier NER steps because it facilitates the recruitment of early NER factors such as XPC and XPA, and, in contrast to yeast, localizes to damaged DNA independently of XPC. Furthermore, INO80 facilitates efficient 64PP and CPD 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 to 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 is repaired.

ISWI

12Several experiments have suggested that ISWI-mediated chromatin remodeling also functions to regulate NER, although its precise role is still unknown. The recombinant Drosophila ISWI, ACF, stimulates NER-mediated excision of 64PP lesions in the linker DNA of reconstituted dinucleosomes, possibly through a nucleosome sliding mechanism. Furthermore, we found that loss of the C. elegans ISWI ATPase isw-1 renders the nematodes sensitive to UV irradiation. Knockdown of the mammalian ISWI ATPase SNF2H/SMARCA5 or its auxiliary factor ACF1/BAZ1A also leads to mild UV sensitivity. Moreover, SNF2H interacts with CSB, and the ACF1 subunit is recruited to UV-induced DNA damage. Further experimentation is required to understand how ISWI chromatin remodeling functions in the UV-DDR.

Discussion and perspectives

13From the above overview, it is clear that some ATP-dependent chromatin-remodeling complexes facilitate the early damage-recognition step of NER (Figure 2), although their precise function and their interdependence is not yet clear. This early chromatin remodeling is in line with the notion that UV-induced increase of DNA accessibility, associated with histone H3 and H4 hyperacetylation, precedes NER. Other results, however, suggest that ATP-dependent chromatin remodeling depends on active NER. Interestingly, it was shown in vitro that not only does SWI/SNF chromatin remodeling stimulate NER, but that NER factors also stimulate chromatin remodeling activity by SWI/SNF. Thus, NER initiation factors and chromatin remodelers may cooperate to stimulate each other's recruitment and activity. The earliest known recognition complex in NER, UV-DDB, was suggested to recruit chromatin-remodeling factors to sites of damage. However, alternative UV-DDB independent mechanisms may also be involved.

14Restoration on DNA of nucleosome occupancy, the loss of which results from DNA damage and its repair, may also require ATP-dependent chromatin remodeling. However, evidence for this function is still limited as to date this has only been observed for INO80 during yeast NER. The yeast and mammalian histone chaperone complex CAF-1 and possibly also ASF1 are involved in this post-repair histone deposition on newly synthesized DNA as well. Further mechanistic studies are required to address whether and how ATP-dependent chromatin remodelers regulate nucleosome occupancy after NER, and to identify the interplay with histone chaperones in this process. Furthermore, because GG-NER and TC-NER utilize alternative DNA damage-recognition mechanisms, it will be interesting to determine differences in chromatin remodeling between these NER sub-pathways, particularly because TC-NER is associated with active transcription, and chromatin is already modified to allow access to proteins. Besides involvement of SWI/SNF and INO80 remodeling complexes, the role of other complexes, such as ISWI and CHD, needs more attention. Based on the analogy to DSB repair (see below), it is expected these complexes are involved in NER as well.

Chromatin and double-strand break repair

15DNA DSBs can be induced by ionizing radiation and chemicals, or can occur as a consequence of replication failure. They represent a major challenge to cells, as they can directly lead to chromosome instability and large genetic alterations. DSBs are mainly repaired by either HR or NHEJ (Figure 3). HR is an error-free repair pathway that preferentially utilizes a sister chromatid as template, which is only present in late S- or G2-phase of the cell cycle, to repair DNA damage. By contrast, NHEJ occurs in all phases of the cell cycle, and fuses broken DNA ends together. Prior to NHEJ-associated ligation, limited DNA end-processing may occur, and this is usually associated with loss of a few nucleotides. NHEJ is therefore a more error-prone repair process than HR. Both DSB repair mechanisms begin with detection of the break and subsequent DNA processing, especially during HR, and these steps are associated with extensive phosphorylation and ubiquitylation events that modify the chromatin and proteins surrounding the break. In the direct vicinity of the break, histone H2AX is phosphorylated by phosphatidylinositol 3-kinases such as ATM and ATR, leading to recruitment of mediator factors, including the scaffold protein MDC1 and the signaling proteins BRCA1 and 53BP1/TP53BP1.

16Chromatin structure plays a major role in DSB repair and signaling. The compaction of chromatin influences the sensitivity of cells to DSBs and the efficiency of the DDR. Furthermore, breaks in heterochromatin are repaired more slowly than in euchromatin and require ATM-dependent phosphorylation of the heterochromatin protein KAP1/TRIM28. Moreover, it has been shown that chromatin becomes more relaxed upon DSB induction and expands locally in an ATP-dependent fashion. It thus appears that the effectiveness of the DSB-associated DDR is tightly regulated by the chromatin structure, and that the process itself modulates chromatin.

ATP-dependent chromatin remodeling during DSB repair

17One of the key proteins in HR, RAD54, contains a functional SWI2/SNF2 ATPase domain that is essential for several of the protein's functions. For instance, through this domain RAD54 promotes branch migration of the holiday junction, an HR intermediate crossstranded DNA structure. Additionally, many other SWI2/SNF2 domain-containing protein complexes function during the DSB-induced DDR (Table 1).

SWI/SNF

18The yeast SWI/SNF complex facilitates the pairing of homologous DNA strands during HR, and is recruited to sites of damage. In addition, the SWI/SNF-related RSC complex in yeast is involved in DSB repair, particularly in HR, in which it is implicated in new DNA synthesis and recombination between sister chromatids during S/G2 phase[ 96]. In addition, RSC functions in NHEJ, because recruitment of the core ATPase of RSC, Sth1, to DSBs depends on the NHEJ-specific DNA end-binding protein yKu70, and two of the RSC subunits interact with yKu80. Conversely, the recruitment of yKu70, the endo/exonuclease Mre11 and the damage-sensor kinases Mec1 and Tel1, and the phosphorylation of H2A at DSBs are also affected by RSC subunits. During DSB repair, RSC locally increases DNA accessibility by nucleosome displacement at the site of damage, which may be a means through which RSC promotes multiple steps of NHEJ and HR.

19Similarly, in mammals SWI/SNF seems to regulate DDR efficiency. Interference with the two SWI/SNF catalytic ATPase subunits BRG1 and BRM sensitizes cells to DSB-inducing agents, impairs damage-induced phosphorylation of H2AX, and decreases repair. Both proteins are recruited to damaged chromatin, and interact with acetylated H3 and H4 in nucleosomes. This interaction is stimulated by phosphorylation of H2AX, and depends on the DNA damage-induced activity of acetyltransferases Gcn5, CBP/CREBBP, and p300/EP300. SWI/SNF recruitment is also facilitated by an increased DNA damage-induced interaction with the early DDR protein BRIT1/MCPH1, which depends on phosphorylation of the SWI/SNF core protein BAF170 by ATM/ATR. Furthermore, BRM is required for Ku70 recruitment to damaged DNA and thus for efficient NHEJ. Together, these results suggest that mammalian SWI/SNF functions to facilitate DSB repair, and is recruited by and stimulates phosphorylation of H2AX (Figure 4).

INO80

20Multiple remodeling activities of INO80 family complexes have been reported to regulate different steps of the DSB-induced DDR. In yeast, the INO80 complex is recruited to DSBs in a H2A-phosphorylation-dependent manner and is required for removal of nucleosomes at DSB sites, affecting both HR and NHEJ. Likewise, the INO80-related SWR1 complex is also recruited to DSBs in a H2A-phosphorylation-dependent manner, where it may function in nucleosome remodeling to regulate DSB repair. INO80 and SWR1 probably function antagonistically in regulating genome integrity and checkpoint adaptation, which is the escape from an extended cell cycle checkpoint. INO80 promotes genome stability and checkpoint escape by exchanging the SWR1-incorporated histone variant Htz for H2A. Other than in yeast, the mammalian INO80 complex is recruited to DSBs independently of phosphorylated H2AX and is implicated in HR, whereas another study has suggested that the core ATPase INO80 and the Arp5 subunit regulate phosphorylation of H2AX. Furthermore, TIP49/RUVBL1 and TIP48/RUVBL2, core subunits of the different mammalian INO80 family complexes, affect RAD51 loading onto DSB sites during HR, but do not affect phosphorylation of H2AX. These findings suggests that INO80 functions during different steps of HR. Apart from a direct role in DSB repair, INO80 might also indirectly function to regulate transcription of the RAD54 and XRCC3 DSB repair genes.

21Several subunits of the mammalian SWR1-related TRRAP-Tip60 complex, including the ATPase p400/EP400 and the acetyltransferase Tip60/KAT5, are recruited to DSBs and locally decrease nucleosome stability. Tip60 acetylates ATM and the histones H2A/H2AX and H4 after DNA damage, and is required for efficient DSB repair. The activity of both p400 and Tip60 is required for subsequent steps of DSB repair, such as ubiquitylation of histones, and recruitment of the signaling proteins BRCA1 and 53BP1. Furthermore, in Drosophila, p400 and Tip60 were both shown to catalyze the exchange of the phosphorylated H2AX homolog H2Av for unmodified H2Av at sites of damage. Together, these results indicate that different chromatin-remodeling complexes in the INO80 family perform different functions in DSB repair to make chromatin more accessible for repair and signaling factors via mechanisms of histone acetylation and nucleosome remodeling (Figure 4).

CHD

22Different members of the CHD family of chromatin remodelers are involved in regulating DSB repair in chromatin. It has been shown that CHD3 is dispersed from DSBs in heterochromatin via a mechanism involving KAP-1 phosphorylation by ATM, leading to chromatin relaxation and heterochromatic DSB repair. CHD3 and the related CHD4 protein can both act as the central ATPase enzyme of the NuRD complex. Loss of several subunits of the CHD4-containing NuRD complex, including CHD4 itself, leads to increased ionizing radiation sensitivity in both C. elegans and mammalian cells and to defective DSB repair. Furthermore, many subunits of NuRD are recruited to DSBs in a, at least for CHD4 and MTA1, poly(ADP ribose) polymerase (PARP)-dependent manner, but surprisingly, do not require phosphorylation of H2AX. Additionally, CHD4 and the regulatory subunit MTA2 function in ubiquitin-mediated signaling by aiding the recruitment of the E3 ligases RNF168 and BRCA1 to DSBs. Finally, CHD4 depletion leads to defects in the G1 to S transition, probably by controlling deacetylation of p53, and in the G2/M checkpoint upon DNA damage. Together, these results suggest an important role for CHD4-containing NuRD in chromatin remodeling at the site of damage, facilitating efficient checkpoint activation (Figure 4).

23Other members of the CHD family that are implicated in the DDR include the CHD1-like ATP-dependent chromatin-remodeling protein ALC1/CHD1L. ALC1 localizes to DSBs in a PARP-dependent manner, and binds the repair proteins Ku70, XRCC1 and DNA-PK. ALC1 also interacts with the damage-recruited histone chaperone and DNA strand-break repair protein APLF, possibly to regulate NHEJ. Finally, mouse cells deficient in CHD2 exhibit increased levels of spontaneous DNA damage, defective DNA-damage signaling, and sensitivity to DNA-damaging agents, suggesting a role for this protein in the DDR.

ISWI

24Multiple ISWI family chromatin-remodeling complexes function in different steps of HR, NHEJ and damage-associated signaling. Both of the ATPases of the ISWI family complexes, SNF2H and SNF2L/SMARCA1, are recruited to DSBs and confer sensitivity to DNA damage upon knockdown. SNF2H is recruited to sites of damage via RNF20-mediated monoubiquitylation of H2B and methylation of H3K4. Depletion of SNF2H impairs DNA end-processing, RAD51 and BRCA1 recruitment, and subsequent repair via HR. Furthermore, the ACF1 protein, which forms part of the mammalian ACF and CHRAC complexes together with SNF2H, accumulates at DSBs and interacts with Ku70. Depletion of ACF1 and other members of the CHRAC complex leads to increased sensitivity to ionizing radiation, to defects in Ku70 and Ku80 recruitment and NHEJ, and to HR. ACF1 is also implicated in controlling the G2/M checkpoint. Another binding partner of SNF2H, WSTF/BAZ1B, which is part of the WICH complex, interacts with and phosporylates H2AX on Tyr142 instead of the canonical damage-induced phosphorylation of Ser139. Importantly, however, depletion of WSTF affects maintenance of H2AX-Ser139 phosporylation and recruitment of active ATM and MDC1 to DSBs. Like SNF2H and ACF1, WSTF is also recruited to DBSs. Together, these data suggest that multiple ISWI chromatin-remodeling complexes act during DSB repair, probably to allow efficient recruitment and maintenance of repair proteins and signaling events (Figure 4).

Discussion and perspectives

25It is clear from the above overview that many different ATP-dependent chromatin-remodeling complexes participate to allow efficient DSB repair and signaling (Figure 4). Although some complexes have been implicated in specific repair events or found to be required for altering nucleosome occupancy of DNA surrounding DBSs, the specific activity of most complexes at sites of damage still remains unclear. Furthermore, contradictory results still cause an ongoing debate as to the exact contribution of these complexes to repair. To resolve these issues, and to answer the emerging question why so many complexes are involved, future studies should be aimed at deciphering their specific molecular activity during subsequent repair steps, and at determining the interdependency of different remodeling processes. This will require a multidisciplinary combination of biochemical and cell-biological analysis, incorporating newly developed quantitative proteomic and microscopy techniques. Together, these studies should provide an integrated view on the function and interplay of the multiple chromatin-remodeling complexes and other chromatin modifications that aid repair efficiency.

Conclusion

26NER and DSB repair are in principle independent pathways, and are initiated by entirely distinct DNA damage-sensing mechanisms. Despite this difference, remarkable similar chromatin modifications (such as H2AX phosphorylation and histone ubiquitylation) and subsequent downstream signaling cascades are triggered by both processes. It is surprising to find that, a similar set of upstream chromatin remodelers is used for both efficient repair of single-strand helix-distorting lesions by NER and for repair of DNA DSBs. This suggests that both for initiation and downstream signaling in distinct repair pathways, similar strategies are used. Despite these similarities, significant differences with respect to chromatin modification are also apparent between HR, NHEJ and NER, which are readily visible at the microscopic level. Specifically, HR factors and downstream signaling molecules form large molecular assemblies on chromatin, referred to as ionizing radiation induced foci, which include chromatin changes that are many kilobases to megabases in length. These microscopic foci are thought to be assembled around DSBs. Strikingly, neither NHEJ nor NER factors form such foci around lesions. Thus, it seems that more or higher-order chromatin modifications are required to allow the complex HR-associated DNA rearrangements, such as homology search, strand annealing, branch migration, and resolution, to occur. This may also be the reason why there are more diverse remodeling complexes in DSB repair. In addition, the repair-patch sizes of NER events are typically around 25 to 30 nucleotides, which is within the range of a single nucleosome, whereas HR involves DNA end-resection and resynthesis of hundreds to thousands of base pairs; therefore it is likely that the latter repair pathway requires more robust chromatin remodeling.

27One of the challenges ahead will be to determine at which steps all the different chromatin remodelers actually function in the DDR (either upstream or downstream of repair and/or signaling), and to what extent they function redundantly or influence each other's function. To obtain an integral view on chromatin remodeling associated with the DDR, a systems-biology approach should be applied, by combining detailed genetic and phenotypic analysis with genomic procedures. Because most of the chromatin remodelers have additional functions outside DDR, particularly in transcription regulation, both genome-wide position and gene-expression analysis will be confounded by the fact that an important part of the DDR network is the transcriptional response branch. Although both transcription and DDR require ATP-dependent chromatin remodeling, both chromatin-associated processes are conceptually rather different. Transcription activation occurs in a site-specific and time-dependent manner, and occurs on a gene with an inherent chromatin structure or compaction. By contrast, repair must be able to occur on all genomic locations, at any time. In transcription regulation, the sequential hierarchy by which chromatin structure is altered is difficult to define. As repair takes place at rather diverse chromatin structures, the general concepts and hierarchical molecular mechanism may perhaps be even more difficult to define.

28It is likely that many chromatin-remodeling complexes have thus far escaped scrutiny because of redundancy or because they only function in specific chromatin environments, which may not lead to a phenotype that is readily identifiable by genetic screens. Future research should aim to determine whether different complexes are involved in repair of different types of chromatin or in different phases of the cell cycle. In addition, as the DDR is tightly regulated in different cell types involving alternative repair pathways, DDR-associated chromatin changes may also be cell-type-specific. It will be interesting to determine to what extent the chromatin landscape and, more specifically, ATP-dependent chromatin-remodeling factors, contribute to DDR differences of different cell types. For instance, we have recently shown that in C. elegans, some SWI/SNF chromatin-remodeling subunits are required only for the response of germ cells to UV, while others play a role only in somatic cells (unpublished results;). Some of the contradictory results or interspecies differences observed to date may in fact reflect such differences in cell type and chromatin involvement. Eventually, knowledge about the role that chromatin plays in the DDR might also help us to better understand the etiology of certain cancers. Both ATP-dependent chromatin remodeling and the DDR are implicated in tumorigenesis, but their interplay in this process is still not understood.

List of abbreviations

2964PP: 6-4 photoproducts; CPD: cyclobutane pyrimidine dimer; DDR: DNA-damage response; DSB: double-strand break; GG-NER: global genome nucleotide excision repair; HR: homologous repair; NER: nucleotide excision repair; NHEJ: non--homologous end-joining; PARP: poly(ADP ribose) polymerase; TC-NER: transcription-coupled nucleotide excision repair.

Competing interests

30The authors declare that they have no competing interests.

Authors' contributions

31HL drafted and edited the manuscript. JAM edited the manuscript and provided artwork. WV helped drafting and edited the manuscript. All authors have read and approved the final manuscript.

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19.
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20.
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Not in our library10.1007/s00018-009-8737-y
21.
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24.
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33.
Alekseev S Kool H Rebel H Fousteri M Moser J Backendorf C de Gruijl FR Vrieling H Mullenders LH Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiationCancer Res2005 651029810306
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34.
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35.
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36.
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38.
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39.
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40.
Mellon I Spivak G Hanawalt PC Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR geneCell1987 51241249
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41.
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42.
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45.
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46.
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Not in our library10.1016/j.molcel.2006.06.029
48.
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49.
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50.
Yu S Owen-Hughes T Friedberg EC Waters R Reed SH The yeast Rad7/Rad16/Abf1 complex generates superhelical torsion in DNA that is required for nucleotide excision repairDNA Repair (Amst)2004 3277287
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51.
Yu S Smirnova JB Friedberg EC Stillman B Akiyama M Owen-Hughes T Waters R Reed SH ABF1-binding sites promote efficient global genome nucleotide excision repairJ Biol Chem2009 284966973
Not in our library10.1074/jbc.m806830200
52.
Yu Y Teng Y Liu H Reed SH Waters R UV irradiation stimulates histone acetylation and chromatin remodeling at a repressed yeast locusProc Natl Acad Sci USA2005 10286508655
Not in our library10.1073/pnas.0501458102
53.
Teng Y Liu H Gill HW Yu Y Waters R Reed SH Saccharomyces cerevisiae Rad16 mediates ultraviolet-dependent histone H3 acetylation required for efficient global genome nucleotide-excision repairEMBO Rep2008 997102
Not in our library10.1038/sj.embor.7401112
54.
Yu S Teng Y Waters R Reed SH How chromatin is remodelled during DNA repair of UV-induced DNA damage in Saccharomyces cerevisiaePLoS Genet2011 7e1002124
Not in our library10.1371/journal.pgen.1002124
55.
Hara R Sancar A The SWI/SNF chromatin-remodeling factor stimulates repair by human excision nuclease in the mononucleosome core particleMol Cell Biol2002 2267796787
Not in our library10.1128/mcb.22.19.6779-6787.2002
56.
Hara R Sancar A Effect of damage type on stimulation of human excision nuclease by SWI/SNF chromatin remodeling factorMol Cell Biol2003 2341214125
Not in our library10.1128/mcb.23.12.4121-4125.2003
57.
Gong F Fahy D Smerdon MJ Rad4-Rad23 interaction with SWI/SNF links ATP-dependent chromatin remodeling with nucleotide excision repairNat Struct Mol Biol2006 13902907
Not in our library10.1038/nsmb1152
58.
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Not in our library10.4161/cc.8.23.10115
59.
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 complexJ Biol Chem2009 2843042430432
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60.
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Not in our library10.4161/cc.7.8.5647
61.
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 phosphorylationMol Cell Biol2009 2962066219
Not in our library10.1128/mcb.00503-09
62.
Klochendler-Yeivin A Picarsky E Yaniv M Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complexMol Cell Biol2006 2626612674
Not in our library10.1128/mcb.26.7.2661-2674.2006
63.
McKenna ES Sansam CG Cho YJ Greulich H Evans JA Thom CS Moreau LA Biegel JA Pomeroy SL Roberts CW Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instabilityMol Cell Biol2008 2862236233
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64.
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65.
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66.
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Not in our library10.1038/nsmb1332
67.
Sarkar S Kiely R McHugh PJ The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damage repairJ Cell Biol2010 19110611068
Not in our library10.1083/jcb.201006178
68.
Czaja W Bespalov VA Hinz JM Smerdon MJ Proficient repair in chromatin remodeling defective ino80 mutants of Saccharomyces cerevisiae highlights replication defects as the main contributor to DNA damage sensitivityDNA Repair (Amst)2010 9976984
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69.
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 pathwayProc Natl Acad Sci USA2010 1071727417279
Not in our library10.1073/pnas.1008388107
70.
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 dinucleosomesEmbo J2001 2020042014
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71.
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 checkpointNucleic Acids Res2011 3919844556
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73.
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Not in our library10.1074/jbc.m600233200
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Luijsterburg MS Dinant C Lans H Stap J Wiernasz E Lagerwerf S Warmerdam DO Lindh M Brink MC Dobrucki JW Heterochromatin protein 1 is recruited to various types of DNA damageJ Cell Biol2009 185577586
Not in our library10.1083/jcb.200810035
75.
Guo R Chen J Mitchell DL Johnson DG GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damageNucleic Acids Res2011 3913901397
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76.
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Gaillard PH Martini EM Kaufman PD Stillman B Moustacchi E Almouzni G Chromatin assembly coupled to DNA repair: a new role for chromatin assembly factor ICell1996 86887896
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Green CM Almouzni G Local action of the chromatin assembly factor CAF-1 at sites of nucleotide excision repair in vivoEMBO J2003 2251635174
Not in our library10.1093/emboj/cdg478
79.
Polo SE Roche D Almouzni G New histone incorporation marks sites of UV repair in human cellsCell2006 127481493
Not in our library10.1016/j.cell.2006.08.049
80.
San Filippo J Sung P Klein H Mechanism of eukaryotic homologous recombinationAnnu Rev Biochem2008 77229257
Not in our library10.1146/annurev.biochem.77.061306.125255
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Kinner A Wu W Staudt C Iliakis G Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatinNucleic Acids Res2008 3656785694
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Not in our library10.1083/jcb.200704140
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86.
Takahashi K Kaneko I Changes in nuclease sensitivity of mammalian cells after irradiation with 60Co gamma-raysInt J Radiat Biol Relat Stud Phys Chem Med1985 48389395
Not in our library10.1080/09553008514551391
87.
Ziv Y Bielopolski D Galanty Y Lukas C Taya Y Schultz DC Lukas J Bekker-Jensen S Bartek J Shiloh Y Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathwayNat Cell Biol2006 8870876
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Kruhlak MJ Celeste A Dellaire G Fernandez-Capetillo O Muller WG McNally JG Bazett-Jones DP Nussenzweig A Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaksJ Cell Biol2006 172823834
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Agarwal S van Cappellen WA Guenole A Eppink B Linsen SE Meijering E Houtsmuller A Kanaar R Essers J ATP-dependent and independent functions of Rad54 in genome maintenanceJ Cell Biol2011 192735750
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Mazin AV Mazina OM Bugreev DV Rossi MJ Rad54, the motor of homologous recombinationDNA Repair (Amst)2010 9286302
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Not in our library10.1038/nature04889
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Not in our library10.1101/gad.1273105
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Sinha M Watanabe S Johnson A Moazed D Peterson CL Recombinational repair within heterochromatin requires ATP-dependent chromatin remodelingCell2009 13811091121
Not in our library10.1016/j.cell.2009.07.013
94.
Koyama H Itoh M Miyahara K Tsuchiya E Abundance of the RSC nucleosome-remodeling complex is important for the cells to tolerate DNA damage in Saccharomyces cerevisiaeFEBS Lett2002 531215221
Not in our library10.1016/s0014-5793(02)03504-4
95.
Shim EY Ma JL Oum JH Yanez Y Lee SE The yeast chromatin remodeler RSC complex facilitates end joining repair of DNA double-strand breaksMol Cell Biol2005 2539343944
Not in our library10.1128/mcb.25.10.3934-3944.2005
96.
Oum JH Seong C Kwon Y Ji JH Sid A Ramakrishnan S Ira G Malkova A Sung P Lee SE Shim EY RSC Facilitates Rad59-Dependent homologous recombination between sister chromatids by promoting cohesin loading at DNA double-strand breaksMol Cell Biol2011
Not in our library10.1128/mcb.01269-10
97.
Shim EY Hong SJ Oum JH Yanez Y Zhang Y Lee SE RSC mobilizes nucleosomes to improve accessibility of repair machinery to the damaged chromatinMol Cell Biol2007 2716021613
Not in our library10.1128/mcb.01956-06
98.
Liang B Qiu J Ratnakumar K Laurent BC RSC functions as an early double-strand-break sensor in the cell's response to DNA damageCurr Biol2007 1714321437
Not in our library10.1016/j.cub.2007.07.035
99.
Kent NA Chambers AL Downs JA Dual chromatin remodeling roles for RSC during DNA double strand break induction and repair at the yeast MAT locusJ Biol Chem2007 2822769327701
Not in our library10.1074/jbc.m704707200
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Park JH Park EJ Lee HS Kim SJ Hur SK Imbalzano AN Kwon J Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX inductionEMBO J2006 2539863997
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Park JH Park EJ Hur SK Kim S Kwon J Mammalian SWI/SNF chromatin remodeling complexes are required to prevent apoptosis after DNA damageDNA Repair (Amst)2009 82939
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102.
Lee HS Park JH Kim SJ Kwon SJ Kwon J A cooperative activation loop among SWI/SNF, gamma-H2AX and H3 acetylation for DNA double-strand break repairEMBO J2010 2914341445
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Ogiwara H Ui A Otsuka A Satoh H Yokomi I Nakajima S Yasui A Yokota J Kohno T Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factorsOncogene2011 3021352146
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104.
Peng G Yim EK Dai H Jackson AP Burgt I Pan MR Hu R Li K Lin SY BRIT1/MCPH1 links chromatin remodelling to DNA damage responseNat Cell Biol2009 11865872
Not in our library10.1038/ncb1895
105.
Morrison AJ Highland J Krogan NJ Arbel-Eden A Greenblatt JF Haber JE Shen X INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repairCell2004 119767775
Not in our library10.1016/j.cell.2004.11.037
106.
van Attikum H Fritsch O Hohn B Gasser SM Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repairCell2004 119777788
Not in our library10.1016/j.cell.2004.11.033
107.
Kawashima S Ogiwara H Tada S Harata M Wintersberger U Enomoto T Seki M The INO80 complex is required for damage-induced recombinationBiochem Biophys Res Commun2007 355835841
Not in our library10.1016/j.bbrc.2007.02.036
108.
Tsukuda T Fleming AB Nickoloff JA Osley MA Chromatin remodelling at a DNA double-strand break site in Saccharomyces cerevisiaeNature2005 438379383
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109.
van Attikum H Fritsch O Gasser SM Distinct roles for SWR1 and INO80 chromatin remodeling complexes at chromosomal double-strand breaksEMBO J2007 2641134125
Not in our library10.1038/sj.emboj.7601835
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Falbo KB Alabert C Katou Y Wu S Han J Wehr T Xiao J He X Zhang Z Shi Y Involvement of a chromatin remodeling complex in damage tolerance during DNA replicationNat Struct Mol Biol2009 1611671172
Not in our library10.1038/nsmb.1686
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Tsukuda T Lo YC Krishna S Sterk R Osley MA Nickoloff JA INO80-dependent chromatin remodeling regulates early and late stages of mitotic homologous recombinationDNA Repair (Amst)2009 8360369
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112.
Papamichos-Chronakis M Krebs JE Peterson CL Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptation in response to DNA damageGenes Dev2006 2024372449
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Downs JA Allard S Jobin-Robitaille O Javaheri A Auger A Bouchard N Kron SJ Jackson SP Cote J Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sitesMol Cell2004 16979990
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Papamichos-Chronakis M Watanabe S Rando OJ Peterson CL Global regulation of H2A.Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrityCell2011 144200213
Not in our library10.1016/j.cell.2010.12.021
115.
Kashiwaba S Kitahashi K Watanabe T Onoda F Ohtsu M Murakami Y The mammalian INO80 complex is recruited to DNA damage sites in an ARP8 dependent mannerBiochem Biophys Res Commun2010 402619625
Not in our library10.1016/j.bbrc.2010.10.066
116.
Kitayama K Kamo M Oma Y Matsuda R Uchida T Ikura T Tashiro S Ohyama T Winsor B Harata M The human actin-related protein hArp5: nucleo-cytoplasmic shuttling and involvement in DNA repairExp Cell Res2009 315206217
Not in our library10.1016/j.yexcr.2008.10.028
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Gospodinov A Tsaneva I Anachkova B RAD51 foci formation in response to DNA damage is modulated by TIP49Int J Biochem Cell Biol2009 41925933
Not in our library10.1016/j.biocel.2008.09.004
118.
Park EJ Hur SK Kwon J Human INO80 chromatin-remodelling complex contributes to DNA double-strand break repair via the expression of Rad54B and XRCC3 genesBiochem J2010 431179187
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Not in our library10.1083/jcb.201001160
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Murr R Loizou JI Yang YG Cuenin C Li H Wang ZQ Herceg Z Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaksNat Cell Biol2006 89199
Not in our library10.1038/ncb1343
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Gorrini C Squatrito M Luise C Syed N Perna D Wark L Martinato F Sardella D Verrecchia A Bennett S Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage responseNature2007 44810631067
Not in our library10.1038/nature06055
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Bird AW Yu DY Pray-Grant MG Qiu Q Harmon KE Megee PC Grant PA Smith MM Christman MF Acetylation of histone H4 by Esa1 is required for DNA double-strand break repairNature2002 419411415
Not in our library10.1038/nature01035
123.
Sun Y Jiang X Chen S Fernandes N Price BD A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATMProc Natl Acad Sci USA2005 1021318213187
Not in our library10.1073/pnas.0504211102
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Sun Y Jiang X Xu Y Ayrapetov MK Moreau LA Whetstine JR Price BD Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60Nat Cell Biol2009 1113761382
Not in our library10.1038/ncb1982
125.
Kusch T Florens L Macdonald WH Swanson SK Glaser RL Yates JR Abmayr SM Washburn MP Workman JL Acetylation by Tip60 is required for selective histone variant exchange at DNA lesionsScience2004 30620842087
Not in our library10.1126/science.1103455
126.
van Haaften G Romeijn R Pothof J Koole W Mullenders LH Pastink A Plasterk RH Tijsterman M Identification of conserved pathways of DNA-damage response and radiation protection by genome-wide RNAiCurr Biol2006 1613441350
Not in our library10.1016/j.cub.2006.05.047
127.
Pegoraro G Kubben N Wickert U Gohler H Hoffmann K Misteli T Ageing-related chromatin defects through loss of the NURD complexNat Cell Biol2009 1112611267
Not in our library10.1038/ncb1971
128.
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