Chromatin modifications and the DNA damage response to ionizing radiation.

0.37 MB·English

by  Kumar, Rakesh

REVIEWARTICLE
published:22January2013
doi:10.3389/fonc.2012.00214
Chromatin modifications and the DNA damage response
to ionizing radiation
RakeshKumar1,NobuoHorikoshi1,MayankSingh1,ArunGupta1,HariS.Misra1,2,KevinAlbuquerque1,
ClaytonR.Hunt1 andTejK.Pandita1*
1DepartmentofRadiationOncology,UniversityofTexasSouthwesternMedicalCenter,Dallas,TX,USA
2HomiBhabhaNationalInstitute,MolecularGeneticsSection,MolecularBiologyDivision,BhabhaAtomicResearchCentre,Mumbai,India
Editedby: In order to survive, cells have evolved highly effective repair mechanisms to deal
MiraJung,GeorgetownUniversity, with the potentially lethal DNA damage produced by exposure to endogenous as well
USA
as exogenous agents. Ionizing radiation exposure induces highly lethal DNA damage,
Reviewedby:
especiallyDNAdouble-strandbreaks(DSBs),thatissensedbythecellularmachineryand
ZhenkunLou,MayoClinic,USA
then subsequently repaired by either of two different DSB repair mechanisms: (1) non-
GasparKitange,MayoClinic,USA
homologousendjoining,whichre-ligatesthebrokenendsoftheDNAand(2)homologous
*Correspondence:
TejK.Pandita,Departmentof recombination, that employs an undamaged identical DNA sequence as a template, to
RadiationOncology,Universityof maintainthefidelityofDNArepair.RepairofDSBsmustoccurwithinthenaturalcontext
TexasSouthwesternMedicalCenter,
of the cellular DNA which, along with specific proteins, is organized to form chromatin,
5323HarryHinesBoulevard,Dallas,
theoverallstructureofwhichcanimpedeDNAdamagesiteaccessbyrepairproteins.The
TX75390,USA.
e-mail:tej.pandita@utsouthwestern. chromatincomplexisadynamicstructureandisknowntochangeasrequiredforongoing
edu cellular processes such as gene transcription or DNA replication. Similarly, during the
processofDNAdamagesensingandrepair,chromatinneedstoundergoseveralchanges
in order to facilitate accessibility of the repair machinery. Cells utilize several factors to
modify the chromatin in order to locally open up the structure to reveal the underlying
DNAsequencebutpost-translationalmodificationofthehistonecomponentsisoneofthe
primary mechanisms. In this review, we will summarize chromatin modifications by the
respectivechromatinmodifyingfactorsthatoccurduringtheDNAdamageresponse.
Keywords:histonemodifications,DNArepair
INTRODUCTION coredomaininteractswithotherhistoneswhiletheterminicon-
Cellsderivedfromindividualswithataxia-telangiectasiaareradia- tain highly conserved, charged lysine and arginine amino acid
tionsensitiveandhaveahigherrateofconversionofDNAdouble- residuesinvolvedinDNA–histoneinteraction.Inadditiontohis-
strand breaks (DSBs) into chromosome breaks post irradiation tones,non-histoneproteinsarealsoinvolvedindevelopingspecial
(PanditaandHittelman,1992a,b;PanditaandRichardson,2009). chromatinstructures.Theknownhistonemodificationsinduced
The increased frequency of chromosome aberrations observed followingionizingradiationexposurearephosphorylation,acety-
in ataxia-telangiectasia mutated (ATM) defective cells has been lation,methylation,andubiquitination(PanditaandRichardson,
attributed to an altered chromatin status which is observed at 2009;Deemetal.,2012).Amongthesemajorchromatinmodifi-
boththeglobalchromatinlevelaswellasspecificallyattelomeric cations,post-damage-inducedhistonephosphorylationhasbeen
chromatin (Pandita and Hittelman, 1995; Smilenov etal., 1999; the most thoroughly studied. Recent studies have provided evi-
Pandita,2001,2002,2003). It is now evident that DNA damage dencethathistoneacetylationoflysineisalsocriticalfortheDDR.
renders chromatin more sensitive to micrococal nuclease diges- Post-translational modifications (PTMs) of histone proteins are
tion(TelfordandStewart,1989)andthatinductionofDSBresults critical for cellular recognition of DNA damage and subsequent
indecondensationofchromatinatthelocalaswellasgloballevel recruitmentofrepairproteincomplexestothedamagesites.More-
(Kruhlak etal., 2006; Dellaire etal., 2009), an essential require- over,evidenceisemergingsuggestingthatpre-existingchromatin
ment for activation of the DNA damage response (DDR) and modifications also play an important role in the DDR (Sharma
subsequent DSB repair. The basic repeating unit of chromatin, etal.,2010).
thenucleosome,consistsof ahistoneoctamercomplexcontain-
ingfourtypesofhistones,namelyH2A,H2B,H3,andH4(Luger HISTONEMODIFICATIONSINDNADSBREPAIR
etal.,1997),aroundwhichiswound146bpofDNA.Nucleosome Histonemodificationsprovidesupportforcriticalrepairproteins
formationcompactsnakeddoublehelicalDNAbyapproximately that act on the DNA damage site by helping in the recruitment
six fold its linear dimension. DSB formation has been reported of specific protein DNA repair factors and also play a role in
to lead to a localized disruption of nucleosomes, a process that sensing the initial DNA damage. Histone modifications have
dependsonNBS1andATM(Berkovichetal.,2007).Histonescon- been detected on lysine as acetylation, methylation, or ubiq-
siststructurallyofaglobularcoredomainwithflexibletailregions uitination modification, on arginine as methylation and on
at both the N-terminal and C-terminal regions. The globular serine/threonine as phosphorylation. Except for ubiquitination,
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all these modifications alter histone/DNA electrostatic interac- and RAD54 that belong to the SWI2/SNF2 family of helicases
tions and ultimately change chromatin dynamics and function involved in DNA repair (Widlak etal., 2006). In addition to
byalteringaccessofthecellularfactorsinvolvedinDDR. H2AX, other histones also undergo phosphorylation as part of
theDDR,e.g.,phosphorylationofH2BatSer14andN-terminal
HISTONEPHOSPHORYLATION phosphorylationofH4(Fernandez-Capetilloetal.,2004a).Phos-
Phosphorylationofallhistoneshasbeenreportedtoaffecttran- phorylation of H2B and H4 has been reported to be abundant
scription,DNArepair,apoptosis,andchromosomecondensation incloseproximitytoendonuclease-induceddouble-strandbreaks
duringmitosis(Hanksetal.,1983;VanHooseretal.,1998).H2A (Cheungetal.,2005;Utleyetal.,2005)andismediatedbysterile
phosphorylationhasbeenextensivelystudiedinresponsetoDNA 20 kinase (Mst1; Ahn etal.,2005) and casein kinase 2 (Cheung
damagingagents(Paulletal.,2000)andphosphorylationspecifi- etal.,2005;Utleyetal.,2005).Themajortypesofphosphorylated
callyoftheH2AvariantH2AXoccursimmediately(withinafew histonesinchromatinandtheassociatedkinasesaresummarized
minutes)afterexposuretoionizingradiation.Phosphorylationof inTable1.
H2AX(Rogakouetal.,1998),theproductbeingreferredtoasγ-
H2AX,has been shown to be an essential event in the response HISTONEMETHYLATION
toDNAstrandbreaksandisthoughttomodifythehigherorder Histonemethylationonlysineandarginine(Grant,2001;Zhang
chromatin structure at the damage site. In yeast, H2A is phos- andReinberg,2001;Fischleetal.,2005;Kouzarides,2007)wasdis-
phorylatedatSer129bytheTel1andMec1kinasesinresponseto covered 40 years ago (Murray, 1964). Specific methylation sites
variousDNAdamagingagents(Kouzarides,2000,2007;Paulletal., linkedtotheDDRaresummarizedinTable2. Multiplemethy-
2000; FosterandDowns,2005)whileinhumansATMandATR lations of H3 and H4 are reported (mono-, di-, and trimethyl
(humanorthologforyeastTel1andMec1,respectively)phospho- groups per residue) at K4, K9, K27, K36, K79 and R2, R8, R17,
rylate the corresponding Ser139 of H2A. This phosphorylation R26forH3andK20andR3forH4.Histonemethyltransferases
event is critical for the recruitment of signaling/repair proteins use S-adenosyl-methionine as a methyl donor for the catalytic
to DNA damage sites since ionizing radiation induced forma- process. Lysine methylation is mainly commenced by the SET
tion of γ-H2AX foci is rapid, precedes repair factor assembly domain containing proteins [Dm Su(var)3-9, Enhancer of zeste
intorepairosomefociandisrequiredforsubsequentfociforma- (E(z)), and trithorax (trx)] while arginine methylation is car-
tion by numerous factors including 53BP1, NBS1, BRCA1, and riedoutbyco-activatorargininemethyltransferase(CARM1)and
MDC1 (reviewed in Fernandez-Capetillo etal.,2004b). In addi- the protein arginine methyl transferase (PRMT1). Additionally,
tion, γ-H2AXhasbeenshowntophysicallyinteractwithNBS1, ashistoneacetylationcanbedetectedbybromodomaincontain-
53BP1, andMDC1anddeficiencyof H2AXresultsinenhanced ingproteins,methylatedsitesaredetectedbyproteinscontaining
genomic instability, further supporting the role of γ-H2AX in a chromodomain motif. Although dimethylation of histone H4
DDR (reviewed in Fernandez-Capetillo etal., 2004b). Ionizing lysine20(H4K20me2),mediatedbythehistonemethyltransferase
radiation (IR)-induced phosphorylation of H2AX occurs in all MMSET(alsoknownasNSD2orWHSC1)inmammals(Peietal.,
phases of the cell cycle, which is consistent with the fact that 2011), does not seem to increase globally after DNA damage,
IR-inducedATM activation occurs in all phases of the cell cycle it is critical for 53BP1 recruitment to double-strand breaks (Pei
(Panditaetal.,2000). Phosphorylationof H2AXfacilitatesdam- etal., 2011) but does increase in the vicinity of DSBs. Not sur-
agesiterecruitmentoftheDDRcomponentMDC1whichbinds prisinglythen, MMSETdepletionsignificantlydecreasesH4K20
to γ-H2AX via its BRCT domain (Yuan etal., 2010). γ-H2AX- methylationatDSBsandthesubsequentaccumulationof53BP1.
recruited MDC1 is phosphorylated byATM as well as by casein Recruitment of MMSET to DSBs requires the γ-H2AX–MDC1
kinase2(Stuckietal.,2005; Louetal.,2006). Bindingof MDC1 pathway; specifically, the interaction between the MDC1 BRCT
to γ-H2AX is further modulated by males absent on the first domainandphosphorylatedSer102ofMMSET(Peietal.,2011).
(MOF)-dependent H4K16 acetylation (Li etal., 2010). Consis- Basedonsuchobservations,itispossiblethatapathwayinvolv-
tentwiththis,H2AXphosphorylationhasbeenshowntofacilitate ingγ-H2AX–MDC1–MMSETregulatestheinductionof H4K20
therecruitmentofSW1/SNFandRSCremodelingcomplexesand methylationonhistonesaroundDSBs,which,inturn,facilitates
several repair proteins including RAD16, CSB/RAD26, RAD5, 53BP1recruitment.
Table1|Phosphorylation.
Modification Modifier Histone RoleinDNArepair Reference
pS139 ATM,ATR, H2AX RecruitsandaccumulatesDDRproteins(MDC1)to Rogakouetal.(1998),Kouzarides(2000,2007),
DNA-PKcs therepairlesionandpromoteshistoneacetylation Paulletal.(2000),FosterandDowns(2005)
pT142 WSTF H2AX RecruitsactivatedATMandMDC1 Cooketal.(2009),Xiaoetal.(2009)
pT14 CK2 H4 PromotesNHEJby53BP1recruitmentand Fernandez-Capetilloetal.(2004a)
methylationofH4K20
pS1 CK2 H4 RoleinDDR Cheungetal.(2005),Utleyetal.(2005)
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Table2|Methylation.
Modification Modifier Histone RoleinDNArepair Reference
K4me3 SET1 H3 StimulatesV(D)Jrecombinationviarecombination Wangetal.(2009),Stanlieetal.(2010)
activatinggene(RAG)complex
K9me3 Suv3-9H1/ H3 InteractswithHP1β,phosphorylates Ayoubetal.(2008),Sunetal.(2009)
Suv3-9H2 damage-inducedHP1β,andactivatesTIP60
K36me2 Metnase/SETMAR H3 AccumulatesNBS1andKutostimulateNHEJ DeHaroetal.(2010),Becketal.(2011)
K79me3 DOT1 H3 RecruitsRAD9inbuddingyeast Bostelmanetal.(2007)
K20me2 Suv4-20H1/Suv4- H4 RecruitsDDRandrepairproteins Sandersetal.(2004), Schottaetal.(2004),
20H2;MMSET Peietal.(2011)
HISTONEACETYLATION N-terminuses of H3 and H4 and at H3K56 plays an important
Histoneacetylationneutralizespositivelychargedlysineresidues, role in genomic stability, DNA replication, and in the binding
altering the chromatin fiber intra- and inter-nucleosomal inter- of chromatinassemblyfactor(CF1)–PCNAcomplex(Chenand
actionstofacilitatedecondensationandenhanceaccesstonucle- Tyler,2008).Acetylationhasbeendetectedatfourlysines(K5,K8,
osomal DNA (Kouzarides,2000; Anderson etal.,2001). Table3 K12,andK16)intheN-terminaltailoftheH4histone.Acetylation
summarizesthehistoneacetylationenzymeswithknownconnec- atK16inH4wasobservedontheDrosophilamaleXchromosome
tionstotheDDRandtheirspecifichistonesubstrates.Acetylation (Turneretal.,1992)andcorrelatedwithgenedosagecompensa-
isadynamichistonemarkerregulatedbythebalancebetweenhis- tion.Themodificationhasalsobeenimplicatedinthecontrolof
tone acetyltransferases (HATs), which transfer an acetyl moiety chromatinstructureresponsibleforinteractionofotherproteins
fromacetyl-coenzymeAtotheε-aminogroupoflysine,andhis- (Shogren-Knaak etal., 2006). The acetyl-transferase responsible
tonedeacetylases(HDACs)whichremovetheacetyl-groupfrom for histone H4 acetylation at K16 is MOF (Gupta etal., 2005,
histones(ShahbazianandGrunstein,2007).Histonemodification 2008; Smith etal.,2005; Sharma etal.,2010). Acetylation at H4
occursinboththenucleusandcytoplasmbyType-AandType-B K16 (H4K16ac) has been implicated in the proper compaction
HATs, respectively. Type-A HATs are responsible for chromatin of chromatin 30-nm fibers (Shogren-Knaak etal., 2006). More
dynamics in the nucleus. There are multiple Type A HAT fam- importantly,lackofMOFalsoinfluencesATMactivation(Gupta
ilies including the GNAT superfamily, MYST family, p300/CBP, etal.,2005) and results in delayed appearance of IR-induced γ-
nuclear receptor co-activators, TAFII250 and TFIIIC. Individ- H2AXfoci(Sharmaetal.,2010).Consistentwiththeinfluenceof
ualhistonescancontainmodificationsthatdifferentiallyregulate histoneH4K16acetylationonATMactivation,HDACinhibitor
chromatin functions. While acetylation of H3 and H4 histones treatmentresultsinglobalATMactivationevenintheabsenceof
increases interactions with components of the transcriptional DNAdamage(BakkenistandKastan,2003).
machinerycontainingbromodomains,methylationoflysine9on
H3(H3K9)allowsheterochromatinprotein1(HP1)bindingvia HISTONEUBIQUITINATION
thechromodomaintothechromatin,therebyinhibitingbinding Ubiquitination is a cellular process that conjugates a 76 amino
of the transcription machinery to DNA. The acetylation at the acid protein, ubiquitin, to the lysine ε-amino group of specific
Table3|Histoneacetylation.
Modification Modifier Histone RoleinDNArepair Reference
K5ac TIP60 H2AX HelpsinK119ubofH2AXandremovalofH2AX Kuschetal.(2004),Ikuraetal.(2007)
fromchromatin
K36ac CBP/p300 H2AX RecruitsKuduringNHEJ Deemetal.(2012)
K9ac,K14ac, GCN5,CBP/p300 H3 RecruitsSW1/SNFcomplex,promotesspreading TamburiniandTyler(2005)
K23acK27ac ofγ-H2AXdomainandregulatesATMactivity
K18ac GCN5,CBP/p300 H3 Regulates Ku protein recruitment during DSB Ogiwaraetal.(2011)
repair
K56ac GCN5,CBP/p300, H3 Depletes after IR to promote NHEJ, enriches Milleretal.(2010)
RTT109 K56acafterHRandUVrepair
K5ac,K8ac, MOF,TIP60-TRRAP; H4 Recruits DDR and repair proteins and recruits Guptaetal.(2005,2008),Sharmaetal.(2010)
K12ac,K16ac CBP/p300 SW1/SNFnucleosomeremodelingcomplex
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proteins as a result of which it acts as a signaling molecule to CHROMATINMODIFICATIONSDURINGNON-HOMOLOGOUS
regulateproteinfunctionandstability.UbiquitinationofH2Aat ENDJOININGREPAIR
K119 is associated with transcriptional repression via polycomb AmajorityofthegenesresponsibleforDSBrepairinhumancells
repressive complex (de Napoles etal., 2004; Fang etal., 2004) have been identified and have been assigned to one of several
and the E3 ubiquitin-protein ligase RNF2 or RING2 responsi- different repair pathways. DNA DSBs induced by IR are mostly
bleforthisubiquitinationisstimulatedbyRINGfinger-domain repaired by either non-homologous end joining (NHEJ) or HR
containing proteins like BMI-1 and RINGIA (Cao etal., 2005). (Cartwright etal., 1998; Jeggo, 1998; Haber, 2000; Rothkamm
Interestingly,BMI-1,RINGIA,andRINGIBareinvolvedinDSB- etal., 2003; Scott and Pandita, 2006; Sonoda etal., 2006; Pan-
associated H2A ubiquitination (Cao and Yan, 2012). Ionizing ditaandRichardson,2009;Chapmanetal.,2012).ForDNADSB
radiation induces ubiquitination of nuclear H2A and H2AX repairbyNHEJ,averylittleornoDNAsequencehomologyatthe
histones. Monoubiquitinated H2A is enriched in the satellite damagedendsisrequired.NHEJinmammaliancellsisthoughtto
regionsofgenomewhereastheubiquitinationofH2Bismostly bethemajorpathwayforDNAdamagerepairafterionizingradia-
in transcriptionally active genes. Histone H2A and H2AX can tionexposure.TherearetwotypesofNHEJrepair:(1)Canonical
also be polyubiquitinated by ubiquitin ligase complex. Dur- endjoiningpathway(C-NHEJ)andthe(2)AlternativeNHEJ(A-
ing DNA repair at the break site, RNF8 and RNF168 catalyze NHEJ)pathway,thelaterbeingaminorDSBrepairpathwaythat
formation of lysine 63 linked polyubiquitination chains on his- works in specific situations such as the absence of Ku. C-NHEJ
tones H2A and H2AX (Doil etal., 2009; Stewart etal., 2009; is essential for both somatic cell survival after IR treatment and
Campbell etal., 2012). RNF8 is rapidly recruited to the sites V(D)J recombination, which generates the antibody and T cell
of DNA damage in an MDC1-dependent manner through its receptor diversity required for lymphocyte maturation (Boboila
functional FHA domain and RNF8 is required to recruit other etal.,2012).BindingoftheringshapedKu70/Ku80heterodimer
repair factors (Huen etal., 2007; Kolas etal., 2007; Mailand (Ku) to both ends of a DSB initiates C-NHEJ at damaged DNA
etal., 2007; Shi etal., 2008; Marteijn etal., 2009; Mok and sitesfollowedbyloadingof DNA-dependentproteinkinasecat-
Henderson,2012). RNF8-catalyzed ubiquitin modification does alytic subunit (DNA-PKcs) onto the DNA-Ku complexes. Prior
not lead to protein degradation because the polyubiquitin syn- to loading of the repair proteins, histone modifications occur
thesized in the RNF8/UBC13-mediated pathways is a lysine-63 which facilitate the recruitment of repair proteins at the dam-
linkage, rather than the lysine-48 canonical signal for protein agesite.DNA-boundKuproteinsserveasatemplateforloading
degradation. Recent studies have revealed that K63Ub synthe- DNA-PKcs which help translocate into the duplex by one heli-
sis is regulated by the deubiquitinating enzyme, OTUB1 (OTU cal turn, leaving DNA-PKcs near the DNA terminus to assist in
domain-containingubiquitinaldehyde-bindingprotein1;Wiener tethering the broken ends together and prevent exonucleolytic
etal., 2012). It is thought that RNF8 executed ubiquitination degradationoftheDNAends(GapudandSleckman,2011).This
has a role in maintaining genomic integrity, however, the role also helps DNA strands search for micro homologies. Activated
of post-damage monoubiquitylation in chromatin reassembly DNA-PKcs phosphorylates different components of the NHEJ
needs to be elucidated (Deem etal.,2012). It has been reported machinery to facilitate end-processing; DNA-PKcs itself under-
thatRNF8isinactivetowardnucleosomalhistoneH2A.Incon- goes autophosphorylation, which helps release DNA-PKcs from
trast RNF168 catalyzes the monoubiquitination of the histones the break site so that subsequent steps of C-NHEJ can occur.
(H2A/H2AX)specificallyonK13-15(Mattirolietal.,2012).Inter- DNA-PK holoenzyme (Ku/DNA-PKcs) recognizes, protects and
estingly, E3 ligases like BRCA1 promote BRCA2 recruitment bridgestheDNAends.DNA-PKconformationalautophosphory-
that appears in turn to promote the recruitment of RAD51 lationisnecessaryforactivationofend-processingenzymes,such
involved in homologous recombination (HR; Qing etal.,2011). as theArtemis nuclease. This complex serves as a docking plat-
Themajorhistonesitesof ubiquitination,theenzymesrequired form for DNA polymerases and ligation factors like DNA ligase
andtheroleof themodificationintheDDRaresummarizedin IVandX-raycrosscomplementingfactor4(XRCC4),whichhelp
Table4. in DNA joining. Cell deficient for the canonical NHEJ proteins
Table4|Ubiquitination.
Modification Modifier Histone RoleinDNArepair Reference
K119ub/K119ub2, RNF8,RNF168 H2A AccumulatesBRAC1and53BP1forDNA Ikuraetal.(2007)
K119poly-ub repair
K119ub/K119ub2, RNF8,RNF168, H2AX RecruitsDDRproteinstotherepairlesion Mailand etal. (2007), Doil etal. (2009),
K119poly-ub TIP60–UBC13 Stewartetal.(2009)
K120ub RNF20–RNF40 H2B RecruitsXRCC4andKuforNHEJand Moyaletal.(2011),Nakamuraetal.(2011)
BRCA1andRAD51FORHR
K91ub BBAP H4 InducesH4K20memodificationand Yanetal.(2009)
recruits53BP1topromoteNHEJ
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undergoDSBrepairbyanalternativeformofNHEJ(AltNHEJ), inchromatinstructureinordertoallowrepairproteinsaccessto
which operates at telomeres in telomerase deficient cells or in damagedDNA.Duringthisprocess,thefirststepistheprocessing
(cid:2)
theabsenceof KuorDNA-PKcs. Thispathwayinvolvesproteins oftheexposedDNAendstoproduce3-overhangingDNAendsfor
differentfromthoseinvolvedintheC-NHEJpathwayincluding RAD51binding.ResectionisfollowedbyRAD51filamentforma-
poly(ADP-ribose)polymerase1(PARP-1),XRCC1,DNAligaseIII tionontheresultingsingle-strandedDNA,homologoussequence
(LIG3), polynucleotide kinase, or Flap endonuclease 1. Though search, heteroduplexformation, repairsynthesis, andresolution
this pathway is relatively poorly characterized, certain features of the heteroduplex, all steps that require major changes in the
of A-NHEJ are well characterized such as a slower kinetics of chromatinstructure.WhileHRmakesasignificantcontribution
DSB repair than in C-NHEJ and competitive repression of A- to cell survival after IR exposure only in the S- and G2-phases,
NHEJ by Ku under normal conditions. Whether C-NHEJ and replication-associated one-ended DSBs are also efficiently and
Alt-NHEJrequireanypathwayspecificchromatinmodificationsis primarilyrepairedbyHR.
(cid:2)
notyetknown. The initiating step for HR is end-resection to create a 3-
Thefirstvisiblechromatinmodificationthatoccursimmedi- overhang,whichissubsequentlycoatedbyreplicationproteinA
ately after cellular exposure to IR is phosphorylation of histone (RPA).Afterformationof aDSBend,theseendsareresectedin
H2AX on Ser139, the product being termed γ-H2AX, which vertebrates by the MRE11/RAD50/NBS1(MRN) complex or the
functionstorecruitrepairproteins.Besidesγ-H2AX,othermod- MRX complex in yeast. Exo1 along with DNA2 nuclease then
(cid:2)
ifications involved in the NHEJ are acetylation, methylation, digest the 5-end in eukaryotes. In yeast, the MRX complex, in
phosphorylation, and ubiquitination of histone H2A,H2B,H3, cooperation with Sae2, is important for initiating DNA resec-
and H4. These histone modifications may play a role in either tion.TheMRNcomplexserveasamultipurposeDNAclampthat
marking the site of a DNA break to facilitate the recruitment acts to directly bridge severed DNA ends. DNA resection is fol-
of DNA repair proteins or relaxing the chromatin so the repair lowedbyacriticalstep,whichisrecognitionofhomologousDNA
proteins can access the damaged DNA site. For example, Met- sequences followed by generation of a joint molecule between
nase, a methylase which dimethylates histone H3 residue K36 single-strandedDNAanditsduplexrepairtemplate.DNAstrand
(H3K36me2)intheDNADSBregion,andthelevelsofH3K36me2 exchangeleadstoswitchingofbase-pairedpartnersbetweenthese
havebeenfoundtocorrespondpositivelytoDSBrepairefficiency DNAs.Homologyrecognitionandstrandexchangearemediated
(reviewed in Williamson etal., 2012). Another modification, byrecombinaseproteinssuchasRecAinprokaryotesandRAD51
H3K4me3,carriedoutbySet1pmethyltransferasehasbeenfound ineukaryotes.RecAandRAD51assembledintoproteinfilaments
atDSBsandtheabsenceof thismodificationhasbeenlinkedto on single-stranded DNA catalyze DNA rearrangement aided by
poorDNADSBrepair(FaucherandWellinger,2010). accessory/mediatorproteins.SubsequentstepsinHRcaninclude
DuringNHEJrepair,histonesH3andH4arereportedlyacety- theengagementofthesecondDNAend,DNAbranchmigration,
lated on the N-terminal lysines (reviewed in Williamson etal., andeventualresolutionofrepairedDNAstrands.
2012).NuA4–TIP60acetylateshistoneH4atDSBsandthisacety- Uponjointmoleculeformation,acriticalcommonstepinthe
(cid:2)
lationhasbeenlinkedwithimprovedDSBrepair(Birdetal.,2002; HRpathwaysisthehandoffofthe3-endoftheincomingDNA
Murr etal., 2006). Similarly, the base levels of H4K16ac prior molecule to a DNA polymerase, such that recombination will
toDNADSBinductioninfluencesrepairascellswithdecreased resultintworestoredduplexDNAs.Atthisstageofthereaction
levels of H4K16ac have reduced efficiency of DNA DSB repair the partner DNA molecules are physically joined via branched
by NHEJ (Sharma etal., 2010). Other histone modifications by DNA structures, which upon ligation can be converted into
INO80,SWR1,andRSCcomplexesarenecessaryforrecruitment so-calledHollidayjunctions.Thereappeartobemanystructure-
ofKu70/80atDNADSBsites(Shimetal.,2007;vanAttikumetal., specificendonucleasesthatcanresolvethesestructuresresulting
2007).ItisinterestingtonotethatatDSBs,RSCcomplexrecruits in the completion of DNA repair by HR. Enzymes such as the
Mre11,whichisfollowedbyATPaseremodelingtofacilitateaccess EscherichiacoliRuvABCcomplexandtheeukaryoticGen1protein
tothesitebyproteinsrequiredforNHEJ-mediatedrepair(Shim incise Holliday junctions producing directly ligatable crossover
etal.,2007).Furthermore,acetylationofH3andH4byCBPand andnon-crossoverproducts.Alternatively,aDNAhelicase,BLM,
p300cooperatewiththeSW1/SNFcomplextofacilitaterecruit- incombinationwithatypeItopoisomerase,canresolveHolliday
mentof Ku70/80(Ogiwaraetal.,2011). Thefunctionof histone junctions.BranchedDNAintermediatesinHRcanalsobeacted
acetylationthereforeseemstobeduringtheearlystagesofNHEJto uponbyevolutionary-conservedstructure-specificendonucleases,
facilitatechromatinrelaxationandsubsequentlyallowtherepair includingMus81/Eme1andSlx1/Slx4. DuringtheHRprocess,a
proteinstoaccesstheDNADSB. numberofacetylationeventsoccuronhistonesH3andH4with
theproteinsimplicatedinthemodificationbeingGCN5,NuA4,
CHROMATINMODIFICATIONSDURINGHOMOLOGOUS andHAT1(TamburiniandTyler,2005;Murretal.,2006).GCN5
RECOMBINATIONREPAIR alsoplayssomeroleinpathwaychoiceforDSBrepairasDNA-PKcs
During the DNA DSB repair by HR, nucleotide sequences are phosphorylatesGCN5toinactivateitsHATdomain.Inaddition,
exchanged between two similar or identical molecules of DNA, GCN5 also interacts with BRCA1 through a mechanism that is
allowingthecellstoaccuratelyrepairDNA.HRtyperepairispre- dependentuponitsHATactivity,suggestingaroleinHRrepairof
dominantduringmeiosisandintheS-andG2-phasesofthecell DNADSBs(Oishietal.,2006).
cycle,whereasNHEJrepairispredominantinG1-phasecells.HR During HR repair, MDC1 recruits RNF8 (E3) to ubiquiti-
repairisacomplexprocess,whichrequiressignificantalterations nate H2AX (Kolas etal., 2007; Mohammad and Yaffe, 2009).
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Kumaretal. HistonemodificationsandDNArepair
Subsequently, recruited BRCA1 further maintains H2AX ubiq- CONCLUSIONANDFUTUREDIRECTIONS
uitinationinordertorecruitdownstreamDDRandDSBrepair WhilethemechanismsbywhichcellsactivatetheDDRandrepair
components.Furthermore,atthecompletionofHRrepairchro- DNAdamagearebecomingclear,muchlessisknownabouthow
matinstructuremustberestoredtothepre-damagestate,aprocess thecellrestoresthepre-damageoriginalchromatinstructureonce
thatstartswithdephosphorylationof γ-H2AXbyproteinphos- damage is repaired. In addition, there is growing evidence that
phatase 2A (PP2A) or PP4C in mammals (Hanks etal., 1983). besides post DNA damage alteration of histone modifications,
Removal of acetylation marks occurs by HDACs, which subse- pre-existinghistonePTMsplayacriticalroleintheDDRandsub-
quentlyresultsinthecondensationofchromatinbacktoitsnative sequentrepair.Histonemodificationpatternschangeduringthe
configuration. inductionofDNADSBaswellasduringtherepairprocess.These
Besidesthechromatinmodifyingfactors,anon-histonechro- changingmodificationsallowthechromatintoopenatthesites
matin protein known as HP1, initially identified in Drosophila ofDNAdamagebutsomemodificationscanholdthechromatin
and named for its predominant localization to pericentric het- inacondensedstate.Pre-existingchromatinmodificationsatthe
erochromatin (Li and Smerdon, 2002), plays a role in genomic histone level can directly affect the initial DDR and subsequent
stability (Sharma etal., 2003). There are three mammalian pathwaychoiceforNHEJandHR.ModificationslikeH4K16acor
HP1 isoforms termed HP1α, HP1β (M31) (Cbx1), and HP1γ H4K20me2regulatedbyMOFandMMSET,respectively,areepi-
,
(M32) (Singh etal., 1991; Eissenberg and Elgin, 2000; Jones geneticmarkersthatcouldactasahistonecodesincetheabsence
etal., 2000). HP1β is a dosage-dependent modifier of pericen- of appropriate markers results both in the loss of a DDR and
tricheterochromatin-inducedsilencing(Festensteinetal.,1999). subsequent repair (Gupta etal.,2005,2008; Sharma etal.,2010;
HP1β plays a critical role in maintaining genomic stability in Hajdu etal., 2011; Bhadra etal., 2012). It will be important to
mammalian cells (Sharma etal., 2003; Aucott etal., 2008) with establishtherelativeimpactof epigeneticchangesinthecontext
both negative (Ayoub etal., 2008; Goodarzi etal., 2008) as ofDNAsequenceandtheirroleinDNADSBrepair.Modulating
well as positive (Luijsterburg etal., 2009) effects on DNA dam- histoneacetylationwithHDACinhibitorscanaltertheIR-induced
age repair. First, damage-dependent phosphorylation of HP1β response resulting in radioprotection as well as radiosensitiza-
decreases its chromodomain-dependent affinity for H3K9me3 tion(CamphausenandTofilon,2007).Smallmoleculeinhibitors
leading to transient displacement of HP1β from DNA dam- of histone modifying enzymes, therefore, represent a promising
age sites (Ayoub etal., 2008). In addition, HP1β depletion meansformodulatingradiotherapyresponse.Aswithotherareas
alleviates the ATM requirement for efficient DSB repair in het- of basic research, understanding the significance of chromatin
erochromatic regions (Goodarzi etal., 2008), suggesting HP1β modificationsashistonecodewillhelptotailorradiotherapybased
suppresses repair in heterochromatic DNA regions. However, onpatientandtumorepigeneticphenotype.
HP1βwasalsofoundtoaccumulateatDNAdamagesites,indi-
cating a more active involvement in DNA repair (Luijsterburg ACKNOWLEDGMENTS
etal., 2009). In human cells, HP1β overexpression increased We thank Jessica Tyler for her insightful thoughts and usage
IR-induced chromosomal damage (Sharma etal., 2003). HP1β of her work. The work in Tej K. Pandita’s laboratory is sup-
mobilization during DNA repair is regulated by ATM-depen- ported by National Institutes of Health National Cancer Insti-
dent KAP-1 Ser473 phosphorylation (Ziv etal.,2006; Bolderson tute Grants R01CA123232, R01CA129537, R01CA154320, and
etal.,2012). U19A1091175.
REFERENCES the DNA damage response. Nature melanogaster. Chromosoma 121, Bostelman,L.J.,Keller,A.M.,Albrecht,
Ahn,S.H.,Cheung,W.L.,Hsu,J.Y., 453,682–686. 79–90. A. M., Arat, A., and Thompson, J.
Diaz,R.L.,Smith,M.M.,andAllis, Bakkenist, C. J., and Kastan, M. B. Bird,A.W.,Yu,D.Y.,Pray-Grant,M. S.(2007).MethylationofhistoneH3
C.D.(2005).Sterile20kinasephos- (2003).DNAdamageactivatesATM G.,Qiu,Q.,Harmon,K.E.,Megee, lysine-79 by Dot1p plays multiple
phorylateshistoneH2Batserine10 through intermolecular autophos- P.C.,etal.(2002).Acetylationofhis- rolesintheresponsetoUVdamagein
during hydrogen peroxide-induced phorylationanddimerdissociation. toneH4byEsa1isrequiredforDNA Saccharomycescerevisiae.DNARepair
apoptosis in S. cerevisiae. Cell 120, Nature421,499–506. double-strand break repair. Nature (Amst.)6,383–395.
25–36. Beck,B.D.,Lee,S.S.,Williamson,E., 419,411–415. Campbell,S.J.,Edwards,R.A.,Leung,
Anderson, L., Henderson, C., and Hromas,R.A.,andLee,S.H.(2011). Boboila, C., Alt, F. W., and Schwer, C. C., Neculai, D., Hodge, C.
Adachi, Y. (2001). Phosphorylation Biochemicalcharacterizationofmet- B. (2012). Classical and alterna- D., Dhe-Paganon, S., etal. (2012).
and rapid relocalization of 53BP1 nase’s endonuclease activity and its tiveend-joiningpathwaysforrepair Molecularinsightsintothefunction
to nuclear foci upon DNA dam- roleinNHEJrepair.Biochemistry50, of lymphocyte-specific and general of RING finger (RNF)-containing
age. Mol. Cell. Biol. 21, 1719– 4360–4370. DNA double-strand breaks. Adv. proteins hRNF8 and hRNF168 in
1729. Berkovich, E., Monnat, R. J. Jr., and Immunol.116,1–49. Ubc13/Mms2-dependentubiquityla-
Aucott,R.,Bullwinkel,J.,Yu,Y.,Shi,W., Kastan, M. B. (2007). Roles of Bolderson,E.,Savage,K.I.,Mahen,R., tion. J. Biol. Chem. 287, 23900–
Billur,M.,Brown,J.P.,etal.(2008). ATMandNBS1inchromatinstruc- Pisupati,V.,Graham,M.E.,Richard, 23910.
HP1-beta is required for develop- ture modulation and DNA double- D.J.,etal.(2012).Kruppel-associated Camphausen, K., and Tofilon, P.
mentof thecerebralneocortexand strandbreakrepair.Nat.CellBiol.9, Box(KRAB)-associatedco-repressor J. (2007). Inhibition of histone
neuromuscularjunctions.J.CellBiol. 683–690. (KAP-1) Ser-473 phosphorylation deacetylation: a strategy for tumor
183,597–606. Bhadra, M. P., Horikoshi, N., Push- regulates heterochromatin pro- radiosensitization.J.Clin.Oncol.25,
Ayoub,N.,Jeyasekharan,A.D.,Bernal, pavallipvalli, S.N., Sarkar, A., Bag, tein 1beta (HP1-beta) mobilization 4051–4056.
J. A., and Venkitaraman, A. R. I., Krishnan, A., etal. (2012). The and DNA repair in heterochro- Cao, J., and Yan, Q. (2012). His-
(2008). HP1-betamobilizationpro- roleofMOFintheionizingradiation matin. J. Biol. Chem. 287, 28122– toneubiquitinationanddeubiquiti-
moteschromatinchangesthatinitiate responseisconservedinDrosophila 28131. nationintranscription,DNAdamage
FrontiersinOncology|RadiationOncology January2013|Volume2|Article214|6
“fonc-02-00214” — 2013/1/19 — 15:46 — page 6 — #6
Kumaretal. HistonemodificationsandDNArepair
response, andcancer. Front. Oncol. Curr. Opin. Genet. Dev. 10, humanMOFinATMfunction.Mol. Li, X., Corsa, C. A., Pan, P. W.,
2:26.doi:10.3389/fonc.2012.00026 204–210. Cell.Biol.25,5292–5305. Wu, L., Ferguson, D., Yu, X., etal.
Cao, R., Tsukada, Y., and Zhang, Y. Fang, J., Chen, T., Chadwick, B., Li, Haber,J.E.(2000).Partnersandpath- (2010). MOF and H4 K16 acetyla-
(2005). Role of Bmi-1 and Ring1A E., and Zhang, Y. (2004). Ring1b- waysrepairingadouble-strandbreak. tion play important roles in DNA
inH2AubiquitylationandHoxgene mediated H2A ubiquitination asso- TrendsGenet.16,259–264. damagerepairbymodulatingrecruit-
silencing.Mol.Cell20,845–854. ciateswithinactiveXchromosomes Hajdu, I., Ciccia, A., Lewis, S. mentofDNAdamagerepairprotein
Cartwright,R.,Dunn,A.M.,Simpson, and is involved in initiation of X M., and Elledge, S. J. (2011). Mdc1. Mol. Cell. Biol. 30, 5335–
P. J., Tambini, C. E., and Thacker, inactivation. J. Biol. Chem. 279, Wolf–Hirschhorn syndrome candi- 5347.
J.(1998). Isolationofnovelhuman 52812–52815. date 1 is involved in the cellular Lou,Z.,Minter-Dykhouse,K.,Franco,
andmousegenesoftherecA/RAD51 Faucher,D.,andWellinger,R.J.(2010). response to DNA damage. Proc. S., Gostissa, M., Rivera, M. A.,
recombination-repair gene family. Methylated H3K4, a transcription- Natl. Acad. Sci. U.S.A.108, 13130– Celeste, A., etal. (2006). MDC1
NucleicAcidsRes.26,1653–1659. associated histone modification, 13134. maintainsgenomicstabilitybypar-
Chapman, J. R., Taylor, M. R., and is involved in the DNA damage Hanks,S.K.,Rodriguez,L.V.,andRao, ticipating in the amplification of
Boulton, S. J. (2012). Playing the response pathway. PLoS Genet. P. N. (1983). Relationship between ATM-dependent DNA damage sig-
endgame:DNAdouble-strandbreak 6:e1001082. doi:10.1371/journal. histonephosphorylationandprema- nals.Mol.Cell21,187–200.
repairpathwaychoice.Mol.Cell47, pgen.1001082 turechromosomecondensation.Exp. Luger,K.,Mader,A.W.,Richmond,R.
497–510. Fernandez-Capetillo, O., Allis, C. D., CellRes.148,293–302. K., Sargent, D. F., and Richmond,
Chen,C.C.,andTyler,J.(2008).Chro- andNussenzweig,A.(2004a).Phos- Huen,M.S.,Grant,R.,Manke,I.,Minn, T.J.(1997).Crystalstructureofthe
matinreassemblysignalstheendof phorylationofhistoneH2BatDNA K.,Yu,X.,Yaffe,M.B.,etal.(2007). nucleosome core particle at 2.8 A
DNArepair.CellCycle7,3792–3797. double-strand breaks. J. Exp. Med. RNF8 transduces the DNA-damage resolution.Nature389,251–260.
Cheung, W. L., Turner, F. B., Krish- 199,1671–1677. signalviahistoneubiquitylationand Luijsterburg,M.S.,Dinant,C.,Lans,H.,
namoorthy, T., Wolner, B., Ahn, S. Fernandez-Capetillo, O., Lee, A., checkpoint protein assembly. Cell Stap,J.,Wiernasz,E.,Lagerwerf,S.,
H., Foley, M., etal. (2005). Phos- Nussenzweig,M.,andNussenzweig, 131,901–914. etal. (2009). Heterochromatinpro-
phorylation of histone H4 serine 1 A. (2004b). H2AX: the histone Ikura, T., Tashiro, S., Kakino, A., tein 1 is recruited to various types
duringDNAdamagerequirescasein guardianofthegenome.DNARepair Shima, H., Jacob, N.,Amunugama, of DNA damage. J. Cell Biol. 185,
kinaseIIinS.cerevisiae. Curr. Biol. (Amst.)3,959–967. R., etal. (2007). DNA damage- 577–586.
15,656–660. Festenstein,R.,Sharghi-Namini,S.,Fox, dependentacetylationandubiquiti- Mailand, N., Bekker-Jensen, S., Faus-
Cook,P.J.,Ju,B.G.,Telese,F.,Wang, M.,Roderick,K.,Tolaini,M.,Norton, nationofH2AXenhanceschromatin trup, H., Melander, F., Bartek, J.,
X., Glass, C.K., andRosenfeld, M. T., etal. (1999). Heterochromatin dynamics.Mol.Cell.Biol.27,7028– Lukas,C.,etal.(2007).RNF8ubiq-
G.(2009). Tyrosinedephosphoryla- protein1modifiesmammalianPEV 7040. uitylates histones at DNA double-
tion of H2AX modulates apoptosis inadose-andchromosomal-context- Jeggo,P.A.(1998).DNAbreakageand strandbreaksandpromotesassembly
and survival decisions. Nature 458, dependentmanner. Nat. Genet. 23, repair.Adv.Genet.38,185–218. ofrepairproteins.Cell131,887–900.
591–596. 457–461. Jones,D.O.,Cowell,I.G.,andSingh, Marteijn,J.A.,Bekker-Jensen,S.,Mai-
Deem, A. K., Li, X., and Tyler, J. Fischle,W.,Tseng,B.S.,Dormann,H. P.B.(2000).Mammalianchromod- land, N., Lans, H., Schwertman,
K. (2012). Epigenetic regulation of L.,Ueberheide,B.M.,Garcia,B.A., omainproteins:theirroleingenome P., Gourdin, A. M., etal. (2009).
genomicintegrity.Chromosoma121, Shabanowitz,J.,etal.(2005).Regu- organisationandexpression. BioEs- Nucleotide excision repair-induced
131–151. lationofHP1-chromatinbindingby says22,124–137. H2Aubiquitinationisdependenton
DeHaro,L.P.,Wray,J.,Williamson,E. histone H3 methylation and phos- Kolas,N.K.,Chapman,J.R.,Nakada, MDC1andRNF8andrevealsauni-
A.,Durant,S.T.,Corwin,L.,Gentry, phorylation.Nature438,1116–1122. S.,Ylanko,J.,Chahwan,R.,Sweeney, versalDNAdamageresponse.J.Cell
A.C.,etal.(2010).Metnasepromotes Foster, E. R., and Downs, J. A. F. D., etal. (2007). Orchestration Biol.186,835–847.
restartandrepairofstalledandcol- (2005). Histone H2A phosphoryla- oftheDNA-damageresponsebythe Mattiroli, F., Vissers, J. H., van Dijk,
lapsedreplicationforks.NucleicAcids tion in DNA double-strand break RNF8 ubiquitin ligase. Science 318, W. J., Ikpa, P., Citterio, E., Ver-
Res.38,5681–5691. repair.FEBSJ.272,3231–3240. 1637–1640. meulen, W., etal. (2012). RNF168
Dellaire, G., Kepkay, R., and Bazett- Gapud, E. J., and Sleckman, B. P. Kouzarides, T. (2000). Acetylation: ubiquitinatesK13-15onH2A/H2AX
Jones,D.P.(2009).Highresolution (2011).Uniqueandredundantfunc- a regulatory modification to rival todriveDNAdamagesignaling.Cell
imagingofchangesinthestructure tionsofATMandDNA-PKcsduring phosphorylation?EMBOJ.19,1176– 150,1182–1195.
and spatial organization of chro- V(D)Jrecombination.CellCycle10, 1179. Miller, K. M., Tjeertes, J. V., Coates,
matin,gamma-H2A.XandtheMRN 1928–1935. Kouzarides,T.(2007).Chromatinmod- J., Legube, G., Polo, S. E., Brit-
complex within etoposide-induced Goodarzi, A. A., Noon, A. T., Deck- ificationsandtheirfunction.Cell128, ton,S.,etal.(2010).HumanHDAC1
DNArepairfoci.CellCycle8,3750– bar, D., Ziv,Y., Shiloh,Y., Lobrich, 693–705. and HDAC2 function in the DNA-
3769. M.,etal.(2008).ATMsignalingfacil- Kruhlak, M. J., Celeste, A., Dellaire, damage response to promote DNA
deNapoles,M.,Mermoud,J.E.,Wakao, itates repair of DNA double-strand G.,Fernandez-Capetillo,O.,Muller, nonhomologous end-joining. Nat.
R.,Tang,Y.A.,Endoh,M.,Appanah, breaks associated with heterochro- W.G., McNally, J.G., etal. (2006). Struct.Mol.Biol.17,1144–1151.
R.,etal.(2004).Polycombgrouppro- matin.Mol.Cell31,167–177. Changesinchromatinstructureand Mohammad, D. H., and Yaffe, M.
teinsRing1A/Blinkubiquitylationof Grant, P. A. (2001). A tale of his- mobilityinlivingcellsatsitesofDNA B. (2009). 14-3-3 proteins, FHA
histoneH2Atoheritablegenesilenc- tonemodifications. GenomeBiol. 2, double-strand breaks. J. Cell Biol. domainsandBRCTdomainsinthe
ingandXinactivation. Dev. Cell 7, REVIEWS0003. 172,823–834. DNAdamageresponse.DNARepair
663–676. Gupta, A., Guerin-Peyrou, T. G., Kusch, T., Florens, L., Macdonald,W. (Amst.)8,1009–1017.
Doil, C., Mailand, N., Bekker-Jensen, Sharma, G. G., Park, C., Agarwal, H., Swanson, S. K., Glaser, R. L., Mok, M. T., and Henderson, B. R.
S., Menard, P., Larsen, D.H., Pep- M.,Ganju,R.K.,etal. (2008). The Yates, J. R. III,etal. (2004). Acety- (2012). Three-dimensional imag-
perkok, R., etal. (2009). RNF168 mammalian ortholog of Drosophila lationbyTip60isrequiredforselec- ing reveals the spatial separation
bindsandamplifiesubiquitinconju- MOFthatacetylateshistoneH4lysine tivehistonevariantexchangeatDNA of gammaH2AX–MDC1–53BP1
gates on damaged chromosomes to 16isessentialforembryogenesisand lesions.Science306,2084–2087. and RNF8–RNF168–BRCA1-A
allow accumulation of repair pro- oncogenesis. Mol. Cell. Biol. 28, Li,S.,andSmerdon,M.J.(2002).Nucle- complexes at ionizing radiation-
teins.Cell136,435–446. 397–409. osome structure and repair of N- inducedfoci.Radiother.Oncol.103,
Eissenberg, J. C., and Elgin, S. C. Gupta, A., Sharma, G. G., Young, C. methylpurinesintheGAL1-10genes 415–420.
(2000). The HP1 protein fam- S.,Agarwal,M.,Smith,E.R.,Paull, of Saccharomyces cerevisiae. J. Biol. Moyal, L., Lerenthal, Y., Gana-Weisz,
ily: getting a grip on chromatin. T. T., etal. (2005). Involvement of Chem.277,44651–44659. M., Mass, G., So, S., Wang, S. Y.,
www.frontiersin.org January2013|Volume2|Article214|7
“fonc-02-00214” — 2013/1/19 — 15:46 — page 7 — #7
Kumaretal. HistonemodificationsandDNArepair
etal. (2011). RequirementofATM- the cell cycle. Oncogene 19, 1386– changesincellgrowthandresponse Miller,E.S.,etal.(2009).TheRID-
dependent monoubiquitylation of 1391. toionizingradiation.Mol.Cell.Biol. DLE syndrome protein mediates a
histoneH2BfortimelyrepairofDNA Pandita, T. K., and Richardson, C. 23,8363–8376. ubiquitin-dependent signaling cas-
double-strandbreaks. Mol. Cell 41, (2009).Chromatinremodelingfinds Sharma,G.G.,So,S.,Gupta,A.,Kumar, cadeatsitesofDNAdamage.Cell136,
529–542. itsplaceintheDNAdouble-strand R.,Cayrou,C.,Avvakumov,N.,etal. 420–434.
Murr, R., Loizou, J. I., Yang, Y. G., breakresponse.NucleicAcidsRes.37, (2010).MOFandhistoneH4acety- Stucki,M.,Clapperton,J.A.,Moham-
Cuenin, C., Li, H., Wang, Z. Q., 1363–1377. lation at lysine 16 are critical for mad, D., Yaffe, M. B., Smerdon,
etal. (2006). Histoneacetylationby Paull,T.T.,Rogakou,E.P.,Yamazaki, DNAdamageresponseanddouble- S. J., and Jackson, S. P. (2005).
Trrap–Tip60 modulates loading of V., Kirchgessner, C.U., Gellert, M., strandbreakrepair. Mol. Cell. Biol. MDC1directlybindsphosphorylated
repair proteins and repair of DNA andBonner,W.M.(2000).Acritical 30,3582–3595. histone H2AX to regulate cellular
double-strandbreaks.Nat.CellBiol. role for histone H2AX in recruit- Shi, W., Ma, Z., Willers, H., Akhtar, responses to DNA double-strand
8,91–99. mentofrepairfactorstonuclearfoci K., Scott, S. P., Zhang, J., etal. breaks.Cell123,1213–1226.
Murray, K.(1964). Theoccurrenceof after DNA damage. Curr. Biol. 10, (2008).DisassemblyofMDC1fociis Sun, Y., Jiang, X., Xu, Y., Ayrapetov,
epsilon-N-methyllysineinhistones. 886–895. controlledbyubiquitin-proteasome- M.K., Moreau, L.A.,Whetstine, J.
Biochemistry3,10–15. Pei,H.,Zhang,L.,Luo,K.,Qin,Y.,Chesi, dependent degradation. J. Biol. R.,etal.(2009).HistoneH3methyla-
Nakamura, K., Kato, A., Kobayashi, M., Fei, F., etal. (2011). MMSET Chem.283,31608–31616. tionlinksDNAdamagedetectionto
J., Yanagihara, H., Sakamoto, regulateshistoneH4K20methylation Shim, E. Y., Hong, S. J., Oum, J. activationofthetumoursuppressor
S., Oliveira, D. V., etal. (2011). and 53BP1 accumulation at DNA H., Yanez, Y., Zhang, Y., and Lee, Tip60.Nat.CellBiol.11,1376–1382.
Regulation of homologous recom- damagesites.Nature470,124–128. S. E. (2007). RSC mobilizes nucle- Tamburini, B. A., and Tyler, J. K.
bination by RNF20-dependent Qing, Y., Yamazoe, M., Hirota, osomes to improve accessibility of (2005).Localizedhistoneacetylation
H2B ubiquitination. Mol. Cell 41, K., Dejsuphong, D., Sakai, W., repair machinery to the damaged and deacetylation triggered by the
515–528. Yamamoto, K. N., etal. (2011). chromatin.Mol.Cell.Biol.27,1602– homologousrecombinationpathway
Ogiwara,H.,Ui,A.,Otsuka,A.,Satoh, The epistatic relationship between 1613. of double-strand DNA repair. Mol.
H., Yokomi, I., Nakajima, S., etal. BRCA2andtheotherRAD51medi- Shogren-Knaak,M.,Ishii,H.,Sun,J.M., Cell.Biol.25,4903–4913.
(2011). HistoneacetylationbyCBP ators in homologous recombina- Pazin,M.J.,Davie,J.R.,andPeter- Telford,D.J.,andStewart,B.W.(1989).
and p300 at double-strand break tion. PLoS Genet. 7:e1002148. doi: son, C.L.(2006). HistoneH4-K16 Micrococcal nuclease: its specificity
sites facilitates SWI/SNF chromatin 10.1371/journal.pgen.1002148 acetylationcontrolschromatinstruc- anduseforchromatinanalysis. Int.
remodeling and the recruitment of Rogakou,E.P.,Pilch,D.R.,Orr,A.H., tureandproteininteractions.Science J.Biochem.21,127–137.
non-homologousendjoiningfactors. Ivanova, V. S., and Bonner, W. M. 311,844–847. Turner,B.M.,Birley,A.J.,andLavender,
Oncogene30,2135–2146. (1998).DNAdouble-strandedbreaks Singh, P. B., Miller, J. R., Pearce, J., J.(1992).HistoneH4isoformsacety-
Oishi, H., Kitagawa, H., Wada, O., inducehistoneH2AXphosphoryla- Kothary, R., Burton, R. D., Paro, latedatspecificlysineresiduesdefine
Takezawa,S.,Tora,L.,Kouzu-Fujita, tiononserine139.J.Biol.Chem.273, R., etal. (1991). A sequence motif individual chromosomes and chro-
M.,etal.(2006).AnhGCN5/TRRAP 5858–5868. found in a Drosophila heterochro- matin domains in Drosophila poly-
histone acetyltransferase complex Rothkamm,K.,Kruger,I.,Thompson, matinproteinisconservedinanimals tenenuclei.Cell69,375–384.
co-activates BRCA1 transactivation L.H.,andLobrich,M.(2003).Path- and plants. Nucleic Acids Res. 19, Utley, R. T., Lacoste, N., Jobin-
function through histone modifica- ways of DNA double-strand break 789–794. Robitaille,O.,Allard,S.,andCote,J.
tion.J.Biol.Chem.281,20–26. repair during the mammalian cell Smilenov,L.B.,Dhar,S.,andPandita,T. (2005).RegulationofNuA4histone
Pandita,T.K.(2001).TheroleofATM cycle. Mol. Cell. Biol. 23, 5706– K.(1999). Alteredtelomerenuclear acetyltransferase activity in tran-
in telomere structure and function. 5715. matrixinteractionsandnucleosomal scriptionandDNArepairbyphos-
Radiat.Res.156,642–647. Sanders, S. L., Portoso, M., Mata, periodicity in ataxia telangiectasia phorylationofhistoneH4.Mol.Cell.
Pandita, T. K. (2002). ATM function J., Bahler, J., Allshire, R. C., and cellsbeforeandafterionizingradi- Biol.25,8179–8190.
andtelomerestability.Oncogene21, Kouzarides,T.(2004).Methylationof ationtreatment. Mol. Cell. Biol. 19, vanAttikum,H.,Fritsch,O.,andGasser,
611–618. histoneH4lysine20controlsrecruit- 6963–6971. S.M.(2007).DistinctrolesforSWR1
Pandita, T. K. (2003). A multifaceted mentofCrb2tositesofDNAdamage. Smith, E. R., Cayrou, C., Huang, R., and INO80 chromatin remodeling
role for ATM in genome mainte- Cell119,603–614. Lane, W.S., Cote, J., andLucchesi, complexesatchromosomaldouble-
nance. Expert Rev. Mol. Med. 5, Schotta, G., Lachner, M., Sarma, K., J.C.(2005).Ahumanproteincom- strand breaks. EMBO J. 26, 4113–
1–21. Ebert, A., Sengupta, R., Reuter, plex homologous to the Drosophila 4125.
Pandita, T. K., and Hittelman, W. N. G., etal. (2004). A silencing path- MSLcomplexisresponsibleforthe VanHooser,A.,Goodrich,D.W.,Allis,
(1992a). The contribution of DNA way to induce H3-K9 and H4-K20 majorityofhistoneH4acetylationat C.D.,Brinkley,B.R.,andMancini,
and chromosome repair deficien- trimethylation at constitutive hete- lysine16.Mol.Cell.Biol.25,9175– M.A.(1998).HistoneH3phospho-
ciestotheradiosensitivityofataxia- rochromatin. GenesDev. 18, 1251– 9188. rylationisrequiredfortheinitiation,
telangiectasia. Radiat. Res. 131, 1262. Sonoda, E., Hochegger, H., Saberi, butnotmaintenance,ofmammalian
214–223. Scott,S.P.,andPandita,T.K.(2006). A., Taniguchi, Y., and Takeda, chromosome condensation. J. Cell
Pandita, T. K., and Hittelman, W. N. ThecellularcontrolofDNAdouble- S. (2006). Differential usage of Sci.111(Pt23),3497–3506.
(1992b). Initial chromosome dam- strand breaks. J. Cell. Biochem. 99, non-homologous end-joining and Wang, G. G., Song, J., Wang, Z.,
agebutnotDNAdamageisgreater 1463–1475. homologousrecombinationindou- Dormann, H. L., Casadio, F., Li,
inataxiatelangiectasiacells. Radiat. Shahbazian, M. D., and Grunstein, blestrandbreakrepair.DNARepair H., etal. (2009). Haematopoietic
Res130,94–103. M.(2007).Functionsofsite-specific (Amst.)5,1021–1029. malignanciescausedbydysregulation
Pandita, T. K., and Hittelman, W. histone acetylation and deacetyla- Stanlie,A.,Aida,M.,Muramatsu,M., ofachromatin-bindingPHDfinger.
N.(1995). Evidenceofachromatin tion. Annu. Rev. Biochem. 76, Honjo,T.,andBegum,N.A.(2010). Nature459,847–851.
basisforincreasedmutagensensitiv- 75–100. Histone3lysine4trimethylationreg- Widlak, P., Pietrowska, M., and
ityassociatedwithmultipleprimary Sharma, G. G., Hwang, K. K., Pan- ulated by the facilitates chromatin Lanuszewska, J.(2006). Theroleof
malignanciesof theheadandneck. dita, R. K., Gupta, A., Dhar, S., transcriptioncomplexiscriticalfor chromatinproteinsinDNAdamage
Int.J.Cancer61,738–743. Parenteau, J., etal. (2003). Human DNAcleavageinclassswitchrecom- recognition and repair. Histochem.
Pandita,T.K.,Lieberman,H.B.,Lim, heterochromatinprotein1isoforms bination.Proc.Natl.Acad.Sci.U.S.A. CellBiol.125,119–126.
D. S., Dhar, S., Zheng, W., Taya, HP1(Hsalpha) and HP1(Hsbeta) 107,22190–22195. Wiener, R., Zhang, X., Wang, T., and
Y., etal. (2000). Ionizing radiation interfere with hTERT–telomere Stewart, G. S., Panier, S., Townsend, Wolberger, C. (2012). The mecha-
activatestheATMkinasethroughout interactions and correlate with K., Al-Hakim, A. K., Kolas, N. K., nismofOTUB1-mediatedinhibition
FrontiersinOncology|RadiationOncology January2013|Volume2|Article214|8
“fonc-02-00214” — 2013/1/19 — 15:46 — page 8 — #8
Kumaretal. HistonemodificationsandDNArepair
of ubiquitination. Nature 483, damage response. Mol. Cell. 36, dependentpathway.Nat.CellBiol.8, K, Hunt CR and Pandita TK (2013)
618–622. 110–120. 870–876. ChromatinmodificationsandtheDNA
Williamson,E.A.,Wray,J.W.,Bansal, Yuan, J., Adamski, R., and Chen, J. damage response to ionizing radiation.
P.,andHromas,R.(2012).Overview (2010). Focus on histone variant Front. Oncol. 2:214. doi: 10.3389/fonc.
forthehistonecodesforDNArepair. H2AX:tobeornottobe.FEBSLett. Conflict of Interest Statement: The 2012.00214
Prog. Mol. Biol. Transl. Sci. 110, 584,3717–3724. authors declare that the research was This article was submitted to Frontiers
207–227. Zhang, Y., and Reinberg, D. (2001). conducted in the absence of any in Radiation Oncology, a specialty of
Xiao,A.,Li,H.,Shechter,D.,Ahn,S.H., Transcription regulation by histone commercial or financial relationships FrontiersinOncology.
Fabrizio,L.A.,Erdjument-Bromage, methylation: interplay between dif- thatcouldbeconstruedasapotential Copyright © 2013 Kumar, Horikoshi,
H.,etal.(2009).WSTFregulatesthe ferentcovalentmodificationsofthe conflictofinterest. Singh,Gupta,Misra,Albuquerque,Hunt
H2A.XDNAdamageresponseviaa core histone tails. Genes Dev. 15, andPandita.Thisisanopen-accessarti-
noveltyrosinekinaseactivity.Nature 2343–2360. Received:21October2012;paperpending cle distributed under the terms of the
457,57–62. Ziv, Y., Bielopolski, D., Galanty, published:05December2012;accepted: CreativeCommonsAttributionLicense,
Yan, Q., Dutt, S., Xu, R., Graves, Y., Lukas, C., Taya, Y., Schultz, 29December2012;publishedonline:22 which permits use, distribution and
K., Juszczynski, P., Manis, J. P., D. C., etal. (2006). Chromatin January2013 reproduction in other forums, provided
etal. (2009). BBAP monoubiqui- relaxation in response to DNA theoriginalauthorsandsourcearecred-
tylates histone H4 at lysine 91 double-strand breaks is modulated Citation:KumarR,HorikoshiN,Singh itedandsubjecttoanycopyrightnotices
and selectively modulates the DNA by a novel ATM- and KAP-1 M, Gupta A, Misra HS, Albuquerque concerninganythird-partygraphicsetc.
www.frontiersin.org January2013|Volume2|Article214|9
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