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Biochimica et Biophysica Acta 1677 (2004) 158–164

Review

Chromatin remodeling and the maintenance of genome integrity

Stephane Allard, Jean-Yves Masson, Jacques Cote*

Centre de Recherche en Cancerologie de l’Universite Laval, Hotel-Dieu de Quebec (CHUQ), 9 rue McMahon, Quebec, Canada G1R 2J6

Received 29 July 2003; received in revised form 6 October 2003; accepted 6 October 2003

Abstract

DNA damage of any type is threatening for a cell. If lesions are left unrepaired, genomic instability can arise, faithful transmission of

genetic information is greatly compromised eventually leading the cell to undergo apoptosis or carcinogenesis. In order to access/detect and

repair these damages, repair factors must circumvent the natural repressive barrier of chromatin. This review will present recent progress

showing the intricate link between chromatin, its remodeling and the DNA repair process. Several studies demonstrated that one of the first

events following specific types of DNA damage is the phosphorylation of histone H2A. This mark or the damage itself are responsible for the

association of chromatin-modifying complexes near damaged DNA. These complexes are able to change the chromatin structure around the

wounded DNA in order to allow the repair machinery to gain access and repair the lesion. Chromatin modifiers include ATP-dependent

remodelers such as SWI/SNF and Rad54 as well as histone acetyltransferases (HATs) like SAGA/NuA4-related complexes and p300/CBP,

which have been shown to facilitate DNA accessibility and repair in different pathways leading to the maintenance of genome integrity.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Chromatin remodeling; DNA repair; Histone acetyltransferase; SWI/SNF; H2AX

1. Introduction

Due to stresses present in their environment (chemical

agents, UV radiation, ionizing radiation) and inherent to

their metabolism (reactive oxygen species, replication prob-

lems), cells could, at any moment, suffer from DNA

damage. If damage is left unrepaired, genomic instability

can arise [1] compromising cell survival. In higher eukar-

yotes, damage that occurs in genes responsible for DNA

repair and/or cell cycle regulation can lead to threatening

diseases including cancer [2–6]. To withstand genotoxic

stress, cells developed several mechanisms by which DNA

damage is detected and repaired [7,8]. It is well known that

histone and non-histone proteins package the eukaryotic

genome into a highly condensed structure termed chromatin.

Hence, enzymatic activities responsible for DNA repair

must circumvent this natural barrier in order to repair

wounds to the genetic material. The nucleosome is the first

level of DNA compaction in the nucleus and is formed by

the wrapping of 147 bp of DNA around a histone octamer

core composed of two H2B–H2B dimers and a H3–H4

0167-4781/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.bbaexp.2003.10.016

* Corresponding author. Tel.: +1-418-525-4444x15545; fax: +1-418-

691-5439.

E-mail address: jacques.cote@crhdq.ulaval.ca (J. Cote).

tetramer [9]. A second level of compaction consists of a

solenoid structure formed by the nucleosomal array and

stabilized by the linker histone H1 [10].

It is well known that such a dense structure greatly

hinders nuclear processes like transcription. To circumvent

this problem, two families of chromatin-modifying enzymes

act on chromatin to make it more accessible to the tran-

scription machinery. The first family acts through covalent

modifications on the histone tails. Phosphorylation, acety-

lation, methylation and ubiquitination are known to be

present on histones and to influence subsequent action of

DNA-or histone-interacting factors [11,12]. Members of the

second family are characterized by their ability to disrupt

histone–DNA contacts in the nucleosomal core using the

energy of ATP hydrolysis. While all ATP-dependent chro-

matin-remodeling complexes possess an ATPase subunit

that belongs to the SWI2/SNF2 superfamily of proteins,

three subclasses are classified according to their sequence

similarities and associated domains: SWI2/SNF2, ISWI and

Mi-2 [13].

By extension, common sense suggests that DNA repair

would also be hindered by chromatin structure. Indeed,

this was confirmed by several recent studies [14–16]. As

for transcription, enzymatic activities responsible for DNA

repair would also need additional players in order to access

the damage and restore chromatin structure after their

S. Allard et al. / Biochimica et Biophysica Acta 1677 (2004) 158–164 159

action. Because mechanisms by which DNA is repaired

greatly vary from one type of damage to another, one can

think that enzymatic machinery required to access chro-

matin would also be lesion-specific. By an expansion of

the original ‘‘access, repair, restore’’ (ARR) model, Green

and Almouzni [17] described factors that may be required

for nucleotide excision repair (NER) and double-strand

break (DSB) repair by homologous recombination (HR). In

that model, NER and HR are shown to require specific

histone acetyltransferase (HAT) activities, ATP-dependent

chromatin-remodeling complexes, chromatin assembly fac-

tors (ACFs) and histone deacetylases (HDAC) to be

effective. Based on recent observations, we can now

extrapolate that model to base excision repair (BER) and

DSB repair by non-homologous end-joining pathway

(NHEJ) since physical and functional interactions have

been shown between these pathways and specific chroma-

tin-modifying activities (see below). In addition, chromatin

modifications (includes ATP-dependent remodeling and

covalent histone modification) and histone variants may

very well play a key dynamic role in targeting/retaining the

DNA repair machinery near DNA lesion sites.

In this review we will discuss recent reports implicating

chromatin reconfiguration in DNA repair processes. We will

focus on the initial steps of DNA repair events and on the

role of chromatin remodeling in helping repair factors to

access damaged DNA. First, we will briefly discuss the

modifications of chromatin itself as an early response to

DNA damage and subsequent repair, beginning at the early

steps following DNA damage to the opening of chromatin.

Then a review of HAT activities implicated in DNA repair

will be presented. Finally, we will focus on ATP-dependent

remodelers of the SWI2/SNF2 family; SWI/SNF itself and

Rad54. These activities have been shown to facilitate DNA

access to other factors and, therefore, repair.

2. Histones: early response factors leading to DNA

repair?

2.1. Histone H2A and variants

The well-known phosphatidylinositol-3 kinase-related

kinase (PIKK) family has a primary role in DNA repair

pathways. Ataxia telangiectasia mutated (ATM), AT-related

(ATR) and DNA-dependent protein kinase (DNA-PK) are

human members of this family. S. cerevisiae homologues of

ATM/ATR, Mec1 and Tel1 are also known to play a central

role in DNA repair. The Ser-Gln-Glu (SQE) motif, known to

be a substrate for these kinases, is present at the C-terminus

of histone H2A in yeast and H2AX (histone variant) in

higher eukaryotes. H2AX is known to be phosphorylated

within minutes following the introduction of DNA DSBs in

the genome (Fig. 1A) [18]. In order to verify if H2A and its

phosphorylation are implicated in DNA repair, Downs and

colleagues tested several mutants for their sensitivity to

DNA-damaging agents. Mutants in which SQE motif is

deleted or mutated display sensitivity to phleomycin and

methyl methane-sulfonate (MMS), drugs that introduce

DSBs in vivo. Moreover, they showed that S129 phosphor-

ylation appears in vivo after MMS or phleomycin treatment

and is dependent on Mec1, the ATR homolog in yeast [19].

This study also demonstrated that H2A phosphorylation is

more likely to be involved in NHEJ rather than HR in yeast.

Redon et al. [20] confirmed the link between DNA repair

and phosphorylation of H2A serine 129 in a study showing

this serine is essential for efficient repair of DNA DSBs

during replication in yeast. While S129 phosphorylation in

yeast seems carried out solely by the ATR homolog, H2AX

is phosphorylated either by ATM or ATR in higher eukar-

yotes. In fact, Burma et al. [21] established that ATM is the

major kinase responsible for histone H2AX phosphorylation

in response to DNA DSBs in murine fibroblasts, while ATR

is also responsible for H2AX phosphorylation following UV

irradiation or replication blocks [22]. A particularly nice

study showed that phosphorylation of H2AX precedes and

initiates focus formation around DSBs by repair-related

factors like the MRN complex (Mre11-Rad50-Nbs1; binds

DNA ends for resection), Brca1 and Rad51 (RecA homo-

log) [23]. These factors appear to assemble sequentially at

the damage site following ionizing radiation. Brca1 forms

foci first, being recruited to the DNA damage site hours

before Rad50 or Rad51. The extent of H2AX phosphoryla-

tion around a single DSB is very large, covering megabases

of chromatin in mammals and kilobases in yeast [18,20] (J.

Downs, S. Allard, N. Bouchard, S.P. Jackson and J. Cote,

submitted). Accordingly, H2AX-deficient cells show in-

creased ionizing radiation sensitivity and genomic instabil-

ity [24].

More recent studies identified proteins that could be

responsible for the interaction with phosphorylated H2AX

(g-H2AX). Nbs1 and 53bp1, known to colocalize with g-

H2AX in vivo at irradiation-induced foci, have been shown

to interact specifically with the phosphorylated form of

H2AX in vitro. While the role of 53bp1 in DNA damage

signaling is clear, its role at the DNA DSB is not well

understood [25]. On the other hand, Nbs1p appears to

recruit Mre11 and Rad50 (MRN complex) to form foci on

damaged sites [26,27]. This recruitment may be required in

order to initiate HR repair pathway implicating Mre11 and

Rad50 or NHEJ by DNA microhomologies [28]. While g-

H2AX is known to form foci within minutes following

DNA damage, Celeste et al. [29] recently showed that this

phosphorylated histone is not required for the initial recruit-

ment of Nbs1, 53bp1 and Brca1 per se. g-H2AX, however,

could be required to concentrate or retain these factors in the

vicinity of DNA lesions.

2.2. Histone H1

A recent report has also highlighted the general effect of

chromatin structure on DNA repair in vivo using a yeast

Fig. 1. Specific recruitment of chromatin modifiers to damaged DNA increases accessibility of the DNA repair machinery to nucleosomal DNA, therefore

improving lesion repair. Schematic representation of damaged DNA and enzymatic machinery shows that DNA damage by itself (red dot represents damage of

any type) or phosphorylation of histone H2A (or histone variant H2AX) could target or concentrate histone modifiers to damage sites. Following their action,

relaxed chromatin is efficiently repaired by the DNA repair machinery and then recondensed by ACFs and HDACs.

S. Allard et al. / Biochimica et Biophysica Acta 1677 (2004) 158–164160

strain deleted for linker histone H1 (Hho1) [30]. This

deletant shows increased HR, reduced average life span

and facilitated recombination-based mechanisms of telo-

mere maintenance, suggesting a strong link between Hho1

and recombination. In addition, Dhho1 strains exhibit in-

creased survival in presence of chemically or endonuclease-

induced DSB damage, therefore demonstrating that Hho1 is

inhibitory to DNA repair by HR in yeast [30].

3. Chromatin-modifying activities in relation with DNA

repair

3.1. HAT complexes

Recently, several links have been established between

chromatin-modifying complexes and DNA repair. Some of

these complexes were noted because they contain eukary-

otic homologues of the bacterial RuvB protein. This protein

is known to be present in complexes responsible for branch

migration during HR and recombination-dependent DNA

repair in prokaryotes [31]. Proteins thought to be homolo-

gous to RuvB have been found in the human Tip60 HAT

complex and the yeast Ino80 ATP-dependent chromatin

remodeling complex [32,33]. The Tip60 HAT complex has

been implicated in the cellular response to DNA damage.

Cells expressing a mutant form of Tip60, lacking HAT

activity, accumulate DSBs upon g-irradiation and fail to

undergo apoptosis [33].

In a more recent study, it was shown that a yeast mutant

lacking the N-terminal acetylable lysines of histone H4 is

sensitive to the DNA-damaging agent MMS and campto-

thecin (CPT), both DSB-inducing agents, but not to UV

radiation, which suggest a specific role of histone H4

acetylation in DSB repair [34]. Moreover, Esa1, the catalytic

subunit of the NuA4 HAT complex, whose substrate is

histone H4, has been shown to be required for DNA DSB

repair. Esa1 is closely related to the human Tip60 protein.

Cells mutated for Esa1 (in which histone H4 acetylation is

abolished or strongly decreased) exhibit the same sensitivity

S. Allard et al. / Biochimica et Biophysica Acta 1677 (2004) 158–164 161

to MMS and CPT than H4 mutants. Again, no sensitivity to

UV radiation was observed. The report by Bird et al. [34]

also showed by chromatin IP (ChIP) that Arp4, a subunit of

the NuA4 complex, is specifically recruited to a DSB site in

vivo. Since NuA4 seemed to preferentially acetylate linear

nucleosomal arrays as compared to circular ones, the

authors suggested that the complex could recognize the

DNA ends at the DSB. Taken together, these results indicate

that acetylation of histone H4 by Esa1 has a crucial and

specific role in DNA DSB repair, apparently more in NHEJ

and a replication-coupled pathway rather than HR [34].

Another connection has been made between NuA4 and

sensitivity to DNA damage via the subunit Yng2 [35], a

tumor suppressor homolog found exclusively in NuA4 [36].

Mutants of YNG2 show sensitivity to agents inducing

replication fork collapse, indicating a role of NuA4 in

intra-S-phase DSB repair, again linked to NHEJ rather than

HR [37]. Recent work from our lab also showed DNA

damage sensitivity of other NuA4 subunit mutants [35,36].

We also detected specific recruitment of Esa1 at a DSB site

in vivo and physically linked it to H2A phosphorylation (J.

Downs, S. Allard, N. Bouchard, S.P. Jackson and J. Cote,

submitted).

In relation to NHEJ in the context of chromatin, Kwon et

al. [38] have shown that V(D)J recombination could require

chromatin modification/remodeling in order to occur. NHEJ

is required to join RAG1/2 endonuclease-generated DSBs in

order to create complete V(D)J coding exons. The in vitro

study used DNA reconstituted into nucleosomes with stan-

dard or hyperacetylated core histones to test cleavage by

RAG1/2 endonucleases [38]. In parallel, effect of remodel-

ing by the human SWI/SNF complex was also tested. Both

histone hyperacetylation and ATP-dependent nucleosome

remodeling were shown to stimulate V(D)J cleavage.

In human, the Gcn5-containing TFTC complex (highly

related to the yeast SAGA complex) has been shown to

contain a 130-kDa protein termed SAP130 (spliceosome-

associated protein 130 [39]) which is 50.7% similar to

DDB1 [40], a component of the UV-damaged DNA-binding

factor [41]. SAP130 and TFTC are preferentially recruited

to UV-damaged DNA. TFTC also binds and acetylates

nucleosomes on UV-damaged DNA more easily than the

ones on intact DNA. Brand et al.’s [41] study also demon-

strated that TFTC subunits are recruited in parallel with the

NER protein XP-A. Furthermore, immunofluorescence

analysis showed that UV irradiation increases H3 acetyla-

tion levels in vivo. All these data taken together suggests

that one function of the TFTC complex would be to

participate in DNA repair [41]. In another report, Martinez

et al. [42] also established a link between DNA repair and a

highly related HAT complex. They detected the presence of

SAP130 in the human STAGA complex but additionally

showed that this complex associates with DDB1 and DDB2

proteins in vitro and in vivo. Both proteins are components

of the UV-damaged DNA-binding factor (UV-DDB). DDB2

binds DNA damage and is implicated in global NER

pathway (see Ref. [43]). Based on STAGA interaction with

UV-DDB, one can speculate that this interaction is respon-

sible for targeting SAGA-like HAT activity to wounded

chromatin sites by direct recognition of the specific type of

DNA damage (Fig. 1B). Chromatin acetylation would then

facilitate binding and/or function of the NER machinery at

the DNA lesion (Fig. 1C and D) [42].

A similar link has been established in BER between the

CBP/p300 HAT and damaged-DNA-interacting factors such

as thymine DNA glycosylase (TDG) and DDB2 (Fig. 1B)

[44,45]. Nilsen et al. [16] have showed that BER is hindered

by nucleosomal structure. More recently, Rubbi and Milner

[46] suggested that detection of transcription-associated

lesions would induce a global chromatin relaxation via the

tumor suppressor p53 and subsequent recruitment of p300.

Chromatin relaxation from the p53-binding sites would

create large areas of accessible chromatin where global

lesion detection and NER could proceed.

Another attractive model for recruitment of HAT activ-

ities could implicate proteins such as 53bp1 and Nbs1,

which could specifically recognize phosphorylation of

H2AX at DNA damage sites (see above). These factors

could bridge phosphorylated histone H2A or H2AX to

histone-modifying complexes (Fig. 1A and B). Indeed, the

NuA4 HAT complex is able to specifically associate with

the phosphorylated C-terminal domain of H2A in vitro (J.

Downs, S. Allard, S.P. Jackson and J. Cote, submitted).

Qin and Parthun [47] recently suggested a link between

acetylation of newly synthesized histones by type B histone

acetyltransferase Hat1 and DNA DSB repair. They demon-

strated that, as for histone H4, mutation of lysine residues on

histone H3 N-terminal tail leads to MMS sensitivity. On the

other hand, specific lysine residues seem more important

than others for the efficient DNA repair. Lysines 14 and 23

seem to function redundantly as presence of either one is

sufficient for cell resistance to MMS. Cells in which the

histone deposition-linked histone acetyltransferase Hat1 has

been mutated also show MMS sensitivity [47]. The specific

defects of these H3 and hat1 mutants are linked to repair of

DSBs by HR. By contrast, histone H4 acetylation mutants

are rather more associated with the NHEJ [34,37] (see

above). It is known that recombinatorial repair of DNA

DSBs requires DNA synthesis. Assembly of this newly

synthesized DNA into chromatin could be compromised

by mutations in histone H3 tail or HAT1. In addition,

mutants of hat1 and asf1, a chromatin assembly factor

already linked to DNA repair [17], show an epistatic

phenotype to DNA damaging agents. It has therefore been

proposed that Hat1 and histone H3 lysine residues are

important for DSB repair at the chromatin assembly step

during/after recombination [47] (Fig. 1D and E).

3.2. ATP-dependent chromatin remodeling complexes

Besides HAT activities, ATP-dependent chromatin re-

modeling complexes have also been recently implicated in

S. Allard et al. / Biochimica et Biophysica Acta 1677 (2004) 158–164162

DNA repair processes. Demonstration was made a few years

ago that Cockayne syndrome B protein (CSB) was required

for coupling NER to transcription. CSB, a DNA-dependent

ATPase of the SWI2/SNF2 family, has been shown to

remodel chromatin substrates in vitro [48]. It is suggested

to facilitate displacement of the stalled polymerase complex

and/or increase accessibility of NER enzymes to the dam-

age. As mentioned in Section 3.1, another RuvB-like-con-

taining complex appears to be involved in the cellular

response to DNA damage. The Ino80 complex contains,

in addition to Rvb1 and Rvb2, an ATPase subunit belonging

to the SWI2/SNF2 superfamily. Cells lacking this subunit

(Ino80) are sensitive to DNA-damaging agents such as

MMS and ionizing radiation [32]. Ura et al. [49] also

demonstrated that the ATP-dependent chromatin-assembly

factor (ACF) facilitates NER on damaged chromatin in

vitro. This Drosophila complex, consisting of ISWI (a

member SWI2/SNF2 superfamily), Acf1 and two other

polypeptides, increases DNA repair by NER especially

when the damage is situated on the linker DNA between

two nucleosomes.

Two research groups recently showed that the original

SWI/SNF complex itself stimulates DNA repair in a nucle-

osomal context [14,15]. Using a 200-bp mononucleosome

fragment, Hara and Sancar [14] demonstrated that acetyla-

minofluorene-guanine (AAF-G) adducts present on that

fragment are more readily removed by excision nuclease

in presence of SWI/SNF complex, while no such facilitation

was observed on naked DNA. Repair stimulation within the

nucleosome core could be explained by an increased acces-

sibility to damage site in the presence of SWI/SNF as shown

by enzyme digestion assay. Moreover, they showed that

repair factors (RPA, XPA and XPC) facilitate the remodel-

ing activity of SWI/SNF, suggesting that these factors could

be functional analogs of transcriptional activators recruiting

remodeling factors to target genes. Based on a model now

accepted for gene transcription [50], it is suggested that

SWI/SNF remodeling could precede or follow binding of

repair factors depending on the nature or site of damage

[14]. While intuition suggests that SWI/SNF would be

specifically recruited to damaged DNA by repair factors,

it could also be present on the site prior to these proteins, in

order to accelerate the assembly of the repair machinery. In

another study, Hara and Sancar [51] demonstrated that the

type of lesion present on DNA modulates SWI/SNF ability

to enhance DNA repair by NER enzymes. In fact, AAF-G

adducts and (6–4) photoproducts are more easily removed

in presence of SWI/SNF while repair of cyclobutane py-

rimidine dimers (CPDs) seems to be unaffected. In contrast,

Gaillard et al. [15] showed that SWI/SNF and ISW2 com-

plexes could facilitate the repair of CPDs through the

photoreactivation pathway. CPDs are not sufficient to dis-

rupt the nucleosomal structure by themselves and a nucle-

osome positioned over a lesion inhibits photoreactivation by

photolyase and T4-endonuclease V. This inhibition is,

however, almost abolished by addition of SWI/SNF to the

reaction. A greater accessibility to the damage site seems

again to be the key to SWI/SNF-enhanced repair. SWI/SNF

and ISW2 are able to remodel at similar rates both intact and

UV-damaged nucleosomes in an ATP-dependent manner

[15]. Finally, a subset of human SWI/SNF complexes have

been found to contain the Brca1 protein, possibly linking

chromatin remodeling to DNA repair foci formation in vivo

[52]. While these in vitro observations suggest a role of

SWI/SNF (and ACF) in DNA repair in vivo, a strong

genetic demonstration of that link has yet to be made.

DSB repair relies heavily on HR in yeast. Several studies

characterized the RAD52 epistasis group of genes as part of

the recombinational repair pathway. In fact, mutations in

any gene of this group have been shown to increase

sensitivity to DSBs [53]. One of the key players in this

group is Rad51, the homologue of bacterial RecA protein.

This protein, responsible for strand invasion during HR, has

been shown to have an increased activity in the presence of

RP-A, Rad55-Rad57 and Rad54. The latter protein contains

a DNA-dependent ATPase domain of the SWI2/SNF2

superfamily. It was recently shown that Rad54 physically

interacts with Rad51-DNA nucleoprotein filaments [54]. In

order to determine the exact role of Rad54 in conjunction

with Rad51, multiple laboratories performed a variety of in

vitro experiments (D-loop formation, strand pairing, nucle-

osome mobility, chromatin remodeling). However, the role

of Rad54 by itself remains controversial. While Alexiadis

and Kadonaga [55] do not detect any chromatin remodeling

activity intrinsic to Rad54 by restriction endonuclease

accessibility assay, Jaskelioff et al. [56] did demonstrate

some activity. Another study by Alexeev et al. [57] showed

that Rad54 is able to mediate nucleosome movement,

though Jaskelioff et al. [56] did not detect any movement

by MNase digestion. Independently of these divergent

conclusions, all studies agreed that association of Rad51

greatly enhances the chromatin remodeling activity of

Rad54 [55–57]. In the model by Jaskelioff et al. [56],

Rad54 would translocate along DNA one nucleotide at a

time, using the energy of ATP hydrolysis. This movement,

in addition to facilitating the homology search process,

could generate superhelical torsion, leading to enhanced

nucleosomal DNA accessibility.

4. Closing remarks

In conclusion, in a fashion very similar to the gene

transcription process, chromatin structure must be remod-

eled to allow access of the necessary proteins to DNA in

order to repair various kinds of damage. Activities are

recruited to the lesion sites and modify the surrounding

chromatin by ATP-dependent remodeling and/or acetyla-

tion of histone N-terminal tails. Furthermore, as in the case

of transcription, chromatin is not only a structural barrier

to overcome in order to access DNA but it also plays a

dynamic regulatory role in the DNA repair process. A

S. Allard et al. / Biochimica et Biophysica Acta 1677 (2004) 158–164 163

nucleosomal histone can carry a specific and localized

posttranslational mark that is recognized by factors and is

required for stable association of the DNA repair machin-

ery. It will be interesting in the future to extend these

discoveries and understand the multiple relationships be-

tween the histone code, chromatin dynamics and DNA

repair.

Acknowledgements

We are grateful to Rhea Utley for correction of the text and

suggestions. Work in our labs has been supported by grants

from the National Cancer Institute of Canada (NCIC) (to J.-

Y.M.), the Canadian Institutes of Health Research (CIHR)

and the Cancer Research Society Inc. (to J.C.). J.-Y.M. is a

CIHR new Investigator and J.C. is a CIHR Investigator.

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