Skip to main content

Advertisement

SpringerLink
Log in

Double-strand breaks and the concept of short- and long-term epigenetic memory

  • Review
  • Published:
Chromosoma Aims and scope Submit manuscript

Abstract

Double-strand breaks represent an extremely cytolethal form of DNA damage and thus pose a serious threat to the preservation of genetic and epigenetic information. Though it is well-known that double-strand breaks such as those generated by ionising radiation are among the principal causative factors behind mutations, chromosomal aberrations, genetic instability and carcinogenesis, significantly less is known about the epigenetic consequences of double-strand break formation and repair for carcinogenesis. Double-strand break repair is a highly coordinated process that requires the unravelling of the compacted chromatin structure to facilitate repair machinery access and then restoration of the original undamaged chromatin state. Recent experimental findings have pointed to a potential mechanism for double-strand break-induced epigenetic silencing. This review will discuss some of the key epigenetic regulatory processes involved in double-strand break (DSB) repair and how incomplete or incorrect restoration of chromatin structure can leave a DSB-induced epigenetic memory of damage with potentially pathological repercussions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abbott DW, Ivanova VS, Wang X, Bonner WM, Ausió J (2001) Characterization of the stability and folding of H2A.Z chromatin particles. J Biol Chem 276:41945–41949

    PubMed  CAS  Google Scholar 

  • Agarwal S, Tafel AA, Kanaar R (2006) DNA double-strand break repair and chromosome translocations. DNA Repair 5:1075–1081

    PubMed  CAS  Google Scholar 

  • Ahnesorg P, Smith P, Jackson SP (2006) XLF interacts with the XRCC4–DNA Ligase IV complex to promote DNA nonhomologous end-joining. Cell 124:301–313

    PubMed  CAS  Google Scholar 

  • Altaf M, Auger A, Covic M, Côté J (2009) Connection between histone H2A variants and chromatin remodeling complexes. Biochem Cell Biol 87:35–50

    PubMed  CAS  Google Scholar 

  • Attwooll CL, Akpinar M, Petrini JHJ (2009) The Mre11 complex and the response to dysfunctional telomeres. Mol Cell Biol 29:5540–5551

    PubMed  CAS  Google Scholar 

  • Ausió J (2006) Histone variants—the structure behind the function. Brief Funct Genomics Proteomics 5:228–243

    Google Scholar 

  • Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR (2008) HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Nature 453:682–686

    PubMed  CAS  Google Scholar 

  • Ayyanathan K, Lechner MS, Bell P, Maul GG, Schultz DC, Yamada Y, Tanaka K, Torigoe K, Rauscher FJ III (2003) Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev 17:1855–1869

    PubMed  CAS  Google Scholar 

  • Azzam EI, de Toledo SM, Little JB (2001) Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from alpha-particle irradiated to non-irradiated cells. Proc Natl Acad Sci USA 98:473–478

    PubMed  CAS  Google Scholar 

  • Azzam EI, de Toledo SM, Spitz DR, Little JB (2002) Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from α-particle-irradiated normal human fibroblast cultures. Cancer Res 62:5436–5442

    PubMed  CAS  Google Scholar 

  • Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    PubMed  CAS  Google Scholar 

  • Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada J, Cigudosa JC, Huang TH, Esteller M (2003) Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO 22:6335–6345

    CAS  Google Scholar 

  • Bao Y, Konesky K, Park Y-J, Rosu S, Dyer PN, Rangasamy D, Tremethick DJ, Laybourn PJ, Luger K (2004) Nucleosomes containing the histone variant H2A.Bbd organize only 118 base pairs of DNA. EMBO J 23:3314–3324

    PubMed  CAS  Google Scholar 

  • Belyakov OV, Malcolmson AM, Folkard M, Prise KM, Michael BD (2001) Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts. Br J Cancer 84:674–679

    PubMed  CAS  Google Scholar 

  • Bennett CB, Lewis LK, Karthikeyan G, Lobachev KS, Jin YH, Sterling JF, Snipe JR, Resnick MA (2001) Genes required for ionizing radiation resistance in yeast. Nat Genet 29:426–434

    PubMed  CAS  Google Scholar 

  • Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

    PubMed  CAS  Google Scholar 

  • Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    PubMed  CAS  Google Scholar 

  • Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces and chromatin. Cell 99:451–454

    PubMed  CAS  Google Scholar 

  • Bird AW, Yu DY, Pray-Grant MG, Qiu Q, Harmon KE, Megee PC, Grant PA, Smith MM, Christman MF (2002) Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419:411–415

    PubMed  CAS  Google Scholar 

  • Boboila C, Jankovic M, Yan CT, Wang JH, Wesemann DR, Zhang T, Fazeli A, Feldman L, Nussenzweig A, Nussenzweig M, Alt FW (2010) Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci USA 107:3034–3039

    PubMed  CAS  Google Scholar 

  • Boeke J, Ammerpohl O, Kegel S, Moehren U, Renkawitz R (2000) The minimal repression domain of MBD2b overlaps with the methyl-CpG-binding domain and binds directly to sin3A. J Biol Chem 275:34963–34967

    PubMed  CAS  Google Scholar 

  • Borde V, Robine N, Lin W, Bonfils S, Géli V, Nicolas A (2009) Histone H3 lysine 4 trimethylation marks meiotic recombination initiation sites. EMBO J 28:99–111

    PubMed  CAS  Google Scholar 

  • Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G. (2006) Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127(7):1361–1373; Dec 29

    Google Scholar 

  • Bouffler S, Blasco M, Cox R, Smith P (2001) Telomeric sequences, radiation sensitivity and genomic instability. Int J Radiat Biol 77:995–1005

    PubMed  CAS  Google Scholar 

  • Bouquet F, Muller C, Salles B (2006) The loss of gammaH2AX signal is a marker of DNA double strand breaks repair only at low levels of DNA damage. Cell Cycle 5:1116–22

    PubMed  CAS  Google Scholar 

  • Bowler D, Moore S, Macdonald D, Smyth S, Clapham P, Kadhim M (2006) Bystander mediated genomic instability after high LET radiation in murine primary haemopoietic stem cells. Mutat Res 597:50–61

    PubMed  CAS  Google Scholar 

  • Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, Khor KC, Nuskey B, Sullivan KE, Pandita TK, Bassing CH, Sleckman BP (2006) ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442:466–470

    PubMed  CAS  Google Scholar 

  • Brickner D, Cajigas I, Fondufe-Mittendorf Y, Ahmed S, Lee P, Widom J, Brickner J (2007) H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. PLoS Biol 5:e81

    PubMed  Google Scholar 

  • Burdak-Rothkamm S, Short SC, Folkard M, Rothkamm K, Prise KM (2006) ATR-dependent radiation-induced [gamma]H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 26:993–1002

    PubMed  Google Scholar 

  • Burdak-Rothkamm S, Rothkamm K, Prise S (2008) ATM acts downstream of ATR in the DNA damage response signalling of bystander cells. Cancer Res 68:7059–7065

    PubMed  CAS  Google Scholar 

  • Cadet J, Delatour T, Douki T, Gasparutto D, Pouget J, Ravanat J, Sauvaigo S (1999) Hydroxyl radicals and DNA base damage. Mutat Res 424:9–21

    PubMed  CAS  Google Scholar 

  • Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Nussenzweig A (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 5:675–679

    PubMed  CAS  Google Scholar 

  • Chadwick B, Willard H (2001) A novel chromatin protein, distantly related to histone H2A, is largely excluded from the inactive X chromosome. J Cell Biol 152:375–384

    PubMed  CAS  Google Scholar 

  • Chai B, Huang J, Cairns BR, Laurent BC (2005) Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers for DNA double-strand break repair. Genes Dev 19:1656–1661

    PubMed  CAS  Google Scholar 

  • Chen CC, Carson JJ, Feser J, Tamburini B, Zabaronick S, Linger J, Tyler JK (2008) Acetylated lysine 56 on histone H3 drives chromatin assembly after repair and signals for the completion of repair. Cell 134:231–243

    PubMed  CAS  Google Scholar 

  • Cheung WL, Turner FB, Krishnamoorthy T, Wolner B, Ahn SH, Foley M, Dorsey JA, Peterson CL, Berger SL, Allis CD (2005) Phosphorylation of histone H4 serine 1 during DNA damage requires casein kinase II in S. cerevisiae. Curr Biol 15:656–660

    PubMed  CAS  Google Scholar 

  • Chi P, Allis CD, Wang GG (2010) Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10:457–469

    PubMed  CAS  Google Scholar 

  • Chodavarapu RK, Feng S, Bernatavichute YV, Chen PY, Stroud H, Yu Y, Hetzel JA, Kuo F, Kim J, Cokus SJ, Casero D, Bernal M, Huijser P, Clark AT, Krämer U, Merchant SS, Zhang X, Jacobsen SE, Pellegrini M (2010) Relationship between nucleosome positioning and DNA methylation. Nature 466:388–392

    PubMed  CAS  Google Scholar 

  • Chowdhury D, Keogh M-C, Ishii H, Peterson CL, Buratowski S, Lieberman J (2005) [gamma]-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell 20:801–809

    PubMed  CAS  Google Scholar 

  • Chowdhury D, Xu X, Zhong X, Ahmed F, Zhong J, Liao J, Dykxhoorn DM, Weinstock DM, Pfeifer GP, Lieberman J (2008) A PP4-phosphatase complex dephosphorylates [gamma]-H2AX generated during DNA replication. Mol Cell 31:33–46

    PubMed  CAS  Google Scholar 

  • Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (1997) Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 277:1996–2000

    PubMed  CAS  Google Scholar 

  • Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumour suppressor. PLoS Biol 6:e301

    Google Scholar 

  • Corpet A, Almouzni G (2009) Making copies of chromatin: the challenge of nucleosomal organization and epigenetic information. Trends Cell Biol 19:29–41

    PubMed  CAS  Google Scholar 

  • Costanzi C, Pehrson JR (1998) Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393:599–601

    PubMed  CAS  Google Scholar 

  • Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Pardo AD, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (2007) DNA damage, homology-directed repair, and DNA methylation. PLoS Genet 3:e110

    PubMed  Google Scholar 

  • Damiani LA, Yingling CM, Leng S, Romo PE, Nakamura J, Belinsky SA (2008) Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Res 21:9005–9014

    Google Scholar 

  • D’Andrea AD, Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3:23–34

    PubMed  Google Scholar 

  • Das C, Lucia MS, Hansen KC, Tyler JK (2009) CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459:113–117

    PubMed  CAS  Google Scholar 

  • Deckbar D, Birraux J, Krempler A, Tchouandong L, Beucher A, Walker S, Stiff T, Jeggo P, Lobrich M (2007) Chromosome breakage after G2 checkpoint release. J Cell Biol 176:749–755

    PubMed  CAS  Google Scholar 

  • Deng Y, Guo X, Ferguson DO, Chang S (2009) Multiple roles for MRE11 at uncapped telomeres. Nature 460:914–918

    PubMed  CAS  Google Scholar 

  • Dhayalan A, Rajavelu A, Rathert P, Tamas R, Jurkowska RZ, Ragozin S, Jeltsch A (2010) The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J Biol Chem 285:26114–26120

    PubMed  CAS  Google Scholar 

  • Dorrance AM, Liu S, Yuan W, Becknell B, Arnoczky KJ, Guimond M, Strout MP, Feng L, Nakamura T, Yu L, Rush LJ, Weinstein M, Leone G, Wu L, Ferketich A, Whitman SP, Marcucci G, Caligiuri MA (2006) MLL partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J Clin Investig 116:2707–2716

    PubMed  CAS  Google Scholar 

  • Dorrance AM, Liu S, Chong A, Pulley B, Nemer D, Guimond M, Yuan W, Chang D, Whitman SP, Marcucci G, Caligiuri MA (2008) The MLL partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele. Blood 112:2508–2511

    PubMed  CAS  Google Scholar 

  • Dover J, Schneider J, Tawiah-Boateng MA, Wood A, Dean K, Johnston M, Shilatifard A (2002) Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J Biol Chem 277:28368–28371

    PubMed  CAS  Google Scholar 

  • Downey M, Durocher D (2006) gammaH2AX as a checkpoint maintenance signal. Cell Cycle 5:1376–81

    PubMed  CAS  Google Scholar 

  • Downs J, Allard S, Jobin-Robitaille O, Javaheri A, Auger A, Bouchard N, Kron S, Jackson S, Côté J (2004) Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol Cell 16:979–90

    PubMed  CAS  Google Scholar 

  • Emerit I, Levy A, Cernjavski L, Arutyunyan R, Oganesyan N, Pogosian A, Mejlumian H, Sarkisian T, Gulkandanian M, Quastel M, Goldsmith J, Riklis E (1994) Transferable clastogenic activity in plasma from persons exposed as salvage personnel of the Chernobyl reactor. J Cancer Res Clin Oncol 120:558–561

    PubMed  CAS  Google Scholar 

  • Emerit I, Quastel M, Goldsmith J, Merkin L, Levy A, Cernjavski L, Alaoui-Youssefi A, Pogossian A, Riklis E (1997) Clastogenic factors in the plasma of children exposed at Chernobyl. Mutat Res 373:47–54

    PubMed  CAS  Google Scholar 

  • Estève PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MR, Pradhan S (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20:3080–3103

    Google Scholar 

  • Fahrner JA, Eguchi S, Herman JG, Baylin SB (2002) Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res 62:7213–7218

    PubMed  CAS  Google Scholar 

  • Fan JY, Gordon F, Luger K, Hansen JC, Tremethick DJ (2002) The essential histone variant H2A.Z regulates the equilibrium between different chromatin conformational states. Nat Struct Biol 9:172–176

    PubMed  CAS  Google Scholar 

  • Faucher D, Wellinger RJ (2010) Methylated H3K4, a transcription-associated histone modification, is involved in the DNA damage response pathway. PLoS Genet 6:e1001082

    PubMed  Google Scholar 

  • Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (2002) DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol 4:993–997

    PubMed  CAS  Google Scholar 

  • Fernandez-Capetillo O, Allis CD, Nussenzweig A (2004) Phosphorylation of histone H2B at DNA double-strand breaks. J Exp Med 199:1671–1677

    PubMed  CAS  Google Scholar 

  • Fouladi B, Sabatier L, Miller D, Pottier G, Murnane J (2000) The relationship between spontaneous telomere loss and chromosome instability in a human tumour cell line. Neoplasia 2:540–54

    PubMed  CAS  Google Scholar 

  • Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Pérez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400

    PubMed  CAS  Google Scholar 

  • Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003a) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278:4035–4040

    PubMed  CAS  Google Scholar 

  • Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003b) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–2312

    PubMed  CAS  Google Scholar 

  • Gilley D, Tanaka H, Hande MP, Kurimasa A, Li GC, Oshimura M, Chen DJ (2001) DNA-PKcs is critical for telomere capping. Proc Natl Acad Sci USA 98:15084–15088

    PubMed  CAS  Google Scholar 

  • Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA (2008) ATM signalling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell 31:167–177

    PubMed  CAS  Google Scholar 

  • Goodhead D (1994) Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol 65:7–17

    PubMed  CAS  Google Scholar 

  • Gupta A, Sharma GG, Young CS, Agarwal M, Smith ER, Paull TT, Lucchesi JC, Khanna KK, Ludwig T, Pandita TK (2005) Involvement of human MOF in ATM function. Mol Cell Biol 25:5292–5305

    PubMed  CAS  Google Scholar 

  • Hada M, Georgakilas AG (2008) Formation of clustered DNA damage after high-LET irradiation: a review. J Radiat Res 49:203–210

    PubMed  CAS  Google Scholar 

  • Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F, Lee C, Almouzni G, Schneider R, Surani MA (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452:877–881

    PubMed  CAS  Google Scholar 

  • Han W, Wu L, Chen S, Bao L, Zhang L, Jiang E, Zhao Y, Xu A, Hei TK, Yu Z (2006) Constitutive nitric oxide acting as a possible intercellular signaling molecule in the initiation of radiation-induced DNA double strand breaks in non-irradiated bystander cells. Oncogene 26:2330–2339

    PubMed  Google Scholar 

  • Hansen KH, Bracken AP, Pasini D, Dietrich N, Gehani SS, Monrad A, Rappsilber J, Lerdrup M, Helin K (2008) A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 10:1291–1300

    PubMed  CAS  Google Scholar 

  • Henikoff S, Furuyama T, Ahmad K (2004) Histone variants, nucleosome assembly and epigenetic inheritance. Trends Genet 20:320–326

    PubMed  CAS  Google Scholar 

  • Höglund E, Blomquist E, Carlsson J, Stenerlöw B (2000) DNA damage induced by radiation of different linear energy transfer: initial fragmentation. Int J Radiat Biol 76:539–47

    PubMed  Google Scholar 

  • Hu B, Wu L, Han W, Zhang L, Chen S, Xu A, Hei TK, Yu Z (2006) The time and spatial effects of bystander response in mammalian cells induced by low dose radiation. Carcinogenesis 27:245–251

    PubMed  CAS  Google Scholar 

  • Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP (2008) Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression. Mol Syst Biol 4:188

    PubMed  Google Scholar 

  • Huang CY, Sharma GG, Walker LM, Bassing CH, Pandita TK, Sleckman BP (2007) Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes. J Exp Med 204:1371–1381

    PubMed  CAS  Google Scholar 

  • Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J (2007) RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131:901–914

    PubMed  CAS  Google Scholar 

  • Huo L, Nagasawa H, Little J (2001) HPRT mutants induced in bystander cells by very low fluences of alpha particles result primarily from point mutations. Radiat Res 156:521–525

    PubMed  CAS  Google Scholar 

  • Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3:276–285

    PubMed  CAS  Google Scholar 

  • Ikura T, Tashiro S, Kakino A, Shima H, Jacob N, Amunugama R, Yoder K, Izumi S, Kuraoka I, Tanaka K, Kimura H, Ikura M, Nishikubo S, Ito T, Muto A, Miyagawa K, Takeda S, Fishel R, Igarashi K, Kamiya K (2007) DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol Cell Biol 27:7028–7040

    PubMed  CAS  Google Scholar 

  • Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G (2004) Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res 104:14–20

    PubMed  CAS  Google Scholar 

  • Ilnytskyy Y, Koturbash I, Kovalchuk O (2009) Radiation-induced bystander effects in vivo are epigenetically regulated in a tissue-specific manner. Environ Mol Mutagen 50:105–113

    PubMed  CAS  Google Scholar 

  • Iwabuchi K, Basu BP, Kysela B, Kurihara T, Shibata M, Guan D, Cao Y, Hamada T, Imamura K, Jeggo PA, Date T, Doherty AJ (2003) Potential role for 53BP1 in DNA end-joining repair through direct interaction with DNA. J Biol Chem 278:36487–36495

    PubMed  CAS  Google Scholar 

  • Jackson V (1988) Deposition of newly synthesized histones: hybrid nucleosomes are not tandemly arranged on daughter DNA strands. Biochemistry 27:2109–2120

    PubMed  CAS  Google Scholar 

  • Jazayeri A, McAinsh AD, Jackson SP (2004) Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair. Proc Natl Acad Sci USA 101:1644–1649

    PubMed  CAS  Google Scholar 

  • Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    PubMed  CAS  Google Scholar 

  • Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191

    PubMed  CAS  Google Scholar 

  • Kadhim M, Macdonald D, Goodhead D, Lorimore S, Marsden S, Wright E (1992) Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 355:738–740

    PubMed  CAS  Google Scholar 

  • Kamakaka RT, Biggins S (2005) Histone variants: deviants? Genes Dev 19:295–316

    PubMed  CAS  Google Scholar 

  • Kass SU, Landsberger N, Wolffe AP (1997) DNA methylation directs a time dependent repression of transcription initiation. Curr Biol 7:157–165

    PubMed  CAS  Google Scholar 

  • Kato T, Okayasu R, Bedford J (2009) Signatures of DNA double strand breaks produced in irradiated G1 and G2 cells persist into mitosis. J Cell Physiol 219:760–765

    PubMed  CAS  Google Scholar 

  • Kaup S, Grandjean V, Mukherjee R, Kapoor A, Keyes E, Seymour CB, Mothersill CE, Schofield PN (2006) Radiation-induced genomic instability is associated with DNA methylation changes in cultured human keratinocytes. Mutat Res 597:87–97

    PubMed  CAS  Google Scholar 

  • Khanna KK (2000) Cancer risk and the ATM gene: a continuing debate. JNCI J Natl Cancer Inst 92:795

    CAS  Google Scholar 

  • Khanna KK, Jackson SP (2001) DNA double-strand breaks: signalling, repair and the cancer connection. Nat Genet 27:247–254

    PubMed  CAS  Google Scholar 

  • Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002) Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J 21:4183–4195

    PubMed  CAS  Google Scholar 

  • Kornberg RD, Lorch Y (1999) Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98:285–294

    PubMed  CAS  Google Scholar 

  • Koturbash I, Rugo RE, Hendricks CA, Loree J, Thibault B, Kutanzi K, Pogribny I, Yanch JC, Engelward BP, Kovalchuk O (2006) Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene 25:4267–4275

    PubMed  CAS  Google Scholar 

  • Koturbash I, Boyko A, Rodriguez-Juarez R, McDonald RJ, Tryndyak VP, Kovalchuk I, Pogribny IP, Kovalchuk O (2007) Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo. Carcinogenesis 28:1831–1838

    PubMed  CAS  Google Scholar 

  • Kouzarides T (2007) Chromatin modifications and their functions. Cell 128:693–705

    PubMed  CAS  Google Scholar 

  • Kuhne M, Riballo E, Rief N, Rothkamm K, Jeggo PA, Lobrich A (2004) A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Cancer Res 64:500–508

    PubMed  Google Scholar 

  • Kundu S, Peterson C (2009) Role of chromatin states in transcriptional memory. Biochim Biophys Acta 1790:445–455

    PubMed  CAS  Google Scholar 

  • Kusch T, Florens L, MacDonald WH, Swanson SK, Glaser RL, Yates JR III, Abmayr SM, Washburn MP, Workman JL (2004) Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 306:2084–2087

    PubMed  CAS  Google Scholar 

  • Laird P, Jaenisch R (2002) DNA methylation and cancer. Hum Mol Genet 3:1487–1495

    Google Scholar 

  • Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex. Science 308:551–554

    PubMed  CAS  Google Scholar 

  • Lee HS, Park JH, Kim SJ, Kwon SJ, Kwon J (2010) A cooperative activation loop among SWI/SNF, γH2AX and H3 acetylation for DNA double-strand break repair. EMBO J 29:1434–1445

    PubMed  CAS  Google Scholar 

  • Lehnert BE, Goodwin EH (1997) Extracellular factor(s) following exposure to alpha particles can cause sister chromatid exchanges in normal human cells. Cancer Res 57:2164–2171

    PubMed  CAS  Google Scholar 

  • Leonhardt H, Page AW, Weier H, Bestor TH (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865–873

    PubMed  CAS  Google Scholar 

  • Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128:707–719

    PubMed  CAS  Google Scholar 

  • Li X, Corsa CA, Pan PW, Wu L, Ferguson D, Yu X, Min J, Dou Y (2010) MOF and H4K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol Cell Biol 30(22):5335–5347

    PubMed  CAS  Google Scholar 

  • Lieber MR, Ma Y, Pannicke U, Schwarz K (2003) Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4:712–720

    PubMed  CAS  Google Scholar 

  • Limoli CL, Kaplan MI, Phillips JW, Adair GM, Morgan WF (1997) Differential induction of chromosomal instability by DNA strand-breaking agents. Cancer Res 57:4048–4056

    PubMed  CAS  Google Scholar 

  • Little JB (2003) Genomic instability and radiation. J Radiol Prot 23:173–181

    PubMed  CAS  Google Scholar 

  • Little J (2006) Cellular radiation effects and the bystander response. Mutat Res 597:113–118

    PubMed  CAS  Google Scholar 

  • Little J, Nagasawa H, Pfenning T, Vetrovs H (1997) Radiation-induced genomic instability: delayed mutagenic and cytogenetic effects of X rays and alpha particles. Radiat Res 148:299–307

    PubMed  CAS  Google Scholar 

  • Liu W, Tanasa B, Tyurina OV, Zhou TY, Gassmann R, Liu WT, Ohgi KA, Benner C, Garcia-Bassets I, Aggarwal AK, Desai A, Dorrestein PC, Glass CK, Rosenfeld MG (2010) PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature 466:508–512

    PubMed  CAS  Google Scholar 

  • Löbrich M, Cooper P, Rydberg B (1996) Non-random distribution of DNA double-strand breaks induced by particle irradiation. Int J Radiat Biol 70:493–503

    PubMed  Google Scholar 

  • Lorimore SA, Kadhim MA, Pocock DA, Papworth D, Stevens DL, Goodhead DT, Wright EG (1998) Chromosomal instability in the descendants of unirradiated surviving cells after α-particle irradiation. Proc Natl Acad Sci USA 95:5730–5733

    PubMed  CAS  Google Scholar 

  • Lorimore SA, Coates PJ, Wright EG (2003) Radiation-induced genomic instability and bystander effects: inter-related nontargeted effects of exposure to ionizing radiation. Oncogene 22:7058–7069

    PubMed  CAS  Google Scholar 

  • Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera MA, Celeste A, Manis JP, van Deursen J, Nussenzweig A, Paull TT, Alt FW, Chen J (2006) MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell 21:187–200

    PubMed  CAS  Google Scholar 

  • Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389:251–260

    PubMed  CAS  Google Scholar 

  • Lyng F, Seymour C, Mothersill C (2002) Initiation of apoptosis in cells exposed to medium from the progeny of irradiated cells: a possible mechanism for bystander-induced genomic instability? Radiat Res 157:365–370

    PubMed  CAS  Google Scholar 

  • Ma Y, Pannicke U, Lu H, Niewolik D, Schwarz K, Lieber MR (2005) The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. J Biol Chem 280:33839–33846

    PubMed  CAS  Google Scholar 

  • Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007) RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131:887–900

    PubMed  CAS  Google Scholar 

  • Mari PO, Florea BI, Persengiev SP, Verkaik NS, Bruggenwirth HT, Modesti M, Giglia-Mari G, Bezstarosti K, Demmers JA, Luider TM, Houtsmuller AB, van Gent DC (2006) Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc Natl Acad Sci USA 103:18597–18602

    PubMed  CAS  Google Scholar 

  • Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370

    PubMed  CAS  Google Scholar 

  • Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Biol 6:838–849

    CAS  Google Scholar 

  • McKittrick E, Gafken PR, Ahmad K, Henikoff S (2004) Histone H3.3 is enriched in covalent modifications associated with active chromatin. Proc Natl Acad Sci USA 101:1525–1530

    PubMed  CAS  Google Scholar 

  • Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404:1–13

    PubMed  CAS  Google Scholar 

  • Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak MA (2005) Can chromosomal instability initiate tumorigenesis? Semin Cancer Biol 15:43–49

    PubMed  CAS  Google Scholar 

  • Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL (2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10:1107–1117

    PubMed  CAS  Google Scholar 

  • Morgan W, Hartmann A, Limoli C, Nagar S, Ponnaiya B (2002) Bystander effects in radiation-induced genomic instability. Mutat Res 504:91–100

    PubMed  CAS  Google Scholar 

  • Morrison AJ, Highland J, Krogan NJ, Arbel-Eden A, Greenblatt JF, Haber JE, Shen X (2004) INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodelling to DNA damage repair. Cell 119:767–788

    PubMed  CAS  Google Scholar 

  • Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H (2005) Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci USA 102:8905–8909

    PubMed  CAS  Google Scholar 

  • Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg Z (2006) Histone acetylation by Trapp-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol 8:91–99

    PubMed  CAS  Google Scholar 

  • Nagar S, Smith LE, Morgan WF (2003) Characterization of a novel epigenetic effect of ionizing radiation: the death-inducing effect. Cancer Res 63:324–328

    PubMed  CAS  Google Scholar 

  • Nagasawa H, Little J (2002) Bystander effect for chromosomal aberrations induced in wild-type and repair deficient CHO cells by low influences of alpha particles. Mutat Res 508:121–129

    PubMed  CAS  Google Scholar 

  • Nakada S, Chen G, Gingras A, Durocher D (2008) PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint. EMBO Rep 9:1019–1026

    PubMed  CAS  Google Scholar 

  • Nan X, Ng HH, Johnson CA, Lahery CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389

    PubMed  CAS  Google Scholar 

  • Narayanan PK, Goodwin EH, Lehnert BE (1997) α-Particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. Cancer Res 57:3963–3971

    PubMed  CAS  Google Scholar 

  • Natarajan AT, Palitti F (2008) DNA repair and chromosomal alterations. Mutat Res, Genet Toxicol Environ Mutagen 657:3–7

    CAS  Google Scholar 

  • Natarajan AT, Berni A, Marimuthu KM, Palitti F (2008) The type and yield of ionising radiation induced chromosomal aberrations depend on the efficiency of different DSB repair pathways in mammalian cells. Mutat Res, Fundam Mol Mech Mutagen 642:80–85

    CAS  Google Scholar 

  • Negishi M, Chiba T, Sarava A, Miyagi S, Iwama A (2009) Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. Genes Cells 14:1347–1357

    PubMed  CAS  Google Scholar 

  • O’Driscoll M, Jeggo PA (2006) The role of double-strand break repair—insights from human genetics. Nat Rev Genet 7:45–54

    PubMed  Google Scholar 

  • O’Hagan HM, Mohammad HP, Baylin SB (2008) Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet 4:e1000155

    PubMed  Google Scholar 

  • Olive PL, Banath JP, Keyes M (2008) Residual gamma H2AX after irradiation of human lymphocytes and monocytes in vitro and its relation to late effects after prostate brachytherapy. Radiother Oncol 86:336–346

    PubMed  CAS  Google Scholar 

  • Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD (2008) DNA methylation inhibitor 5-aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol 28:752–771

    PubMed  CAS  Google Scholar 

  • Pant G, Kamada N (1977) Chromosome aberrations in normal leukocytes induced by the plasma of exposed individuals. Hiroshima J Med Sci 26:149–154

    PubMed  CAS  Google Scholar 

  • Park Y, Luger K (2008) Histone chaperones in nucleosome eviction and histone exchange. Curr Opin Struct Biol 18:282–289

    PubMed  Google Scholar 

  • Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN, Kwon J (2006) Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO J 25:3986–3997

    PubMed  CAS  Google Scholar 

  • Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TBL, von Zglinicki T (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347

    PubMed  Google Scholar 

  • Pennings S, Allan J, Davey CS (2005) DNA methylation, nucleosome formation and positioning. Brief Funct Genomics Proteomics 3:351–361

    CAS  Google Scholar 

  • Pilch DR, Sedelnikova OA, Redon C, Celeste A, Nussenzweig A, Bonner WM (2003) Characteristics of gamma-H2AX foci at DNA double-strand break sites. Biochem Cell Biol 81:123–129

    PubMed  CAS  Google Scholar 

  • Polo SE, Roche D, Almouzni G (2006) New histone incorporation marks sites of UV repair in human cells. Cell 127:481–493

    PubMed  CAS  Google Scholar 

  • Pouget J-P, Mather SJ (2001) General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med 28:541–561

    PubMed  CAS  Google Scholar 

  • Pradhan S, Bacolla A, Wells RD, Roberts RJ (1999) Recombinant human DNA (cytosine-5) methyltransferase I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem 274:33002–33010

    PubMed  CAS  Google Scholar 

  • Prise KM, Folkard M, Michael BB (2003) A review of the bystander effect and its implications for low-dose exposure. Radiat Prot Dosim 104:347–355

    CAS  Google Scholar 

  • Probst AV, Dunleavy E, Almouzni G (2009) Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol 10:192–206

    PubMed  CAS  Google Scholar 

  • Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, Baylin SB (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2:e40

    PubMed  Google Scholar 

  • Rich T, Allen RL, Wyllie AH (2000) Defying death after DNA damage. Nature 407:777–783

    PubMed  CAS  Google Scholar 

  • Richardson C, Horikoshi N, Pandita TK (2004) The role of the DNA double-strand break response network in meiosis. DNA Repair 3:1149–1164

    PubMed  CAS  Google Scholar 

  • Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 97:10014–10019

    PubMed  CAS  Google Scholar 

  • Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumours. Nucleic Acids Res 11:2291–2298

    Google Scholar 

  • Rodier F, Coppé JP, Patil CK, Hoeijmakers WAM, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979

    PubMed  CAS  Google Scholar 

  • Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273:5858–5868

    PubMed  CAS  Google Scholar 

  • Rogakou EP, Boon C, Redon C, Bonner WM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146:905–916

    PubMed  CAS  Google Scholar 

  • Rothkamm K, Kruger I, Thompson LH, Lobrich M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23:5706–5715

    PubMed  CAS  Google Scholar 

  • Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269–277

    PubMed  CAS  Google Scholar 

  • Ruhl DD, Jin J, Cai Y, Swanson S, Florens L, Washburn MP, Conaway RC, Conaway JW, Chrivia JC (2006) Purification of a human SRCAP complex that remodels chromatin by incorporating the histone variant H2A.Z into nucleosomes. Biochemistry 45:5671–5677

    PubMed  CAS  Google Scholar 

  • Saha A, Wittmeyer J, Cairns BR (2006) Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 7:437–447

    PubMed  CAS  Google Scholar 

  • Schermelleh L, Haemmer A, Spada F, Rösing N, Meilinger D, Rothbauer U, Cardoso MC, Leonhardt H (2007) Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation. Nucleic Acids Res 35:4301–4312

    PubMed  CAS  Google Scholar 

  • Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, Bergman Y, Simon I, Cedar H (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 29:232–236

    Google Scholar 

  • Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E, Celeste A, Pagani M, Opravil S, De La Rosa-Veazquez IA, Espejo A, Bedford MT, Nussenzweig A, Busslinger M, Jenuwein T (2008) A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev 22:2048–2061

    PubMed  CAS  Google Scholar 

  • Schwartz BE, Ahmad K (2005) Transcriptional activation triggers deposition and removal of the histone variant H3.3. Genes Dev 19:804–814

    PubMed  CAS  Google Scholar 

  • Sedelnikova OA, Rogakou EP, Panyutin IG, Bonner WM (2002) Quantitative detection of (125) IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiat Res 158:486–492

    PubMed  CAS  Google Scholar 

  • Sedelnikova OA, Pilch DR, Redon C, Bonner WM (2003) Histone H2AX in DNA damage and repair. Cancer Biol Ther 2:233–235

    PubMed  CAS  Google Scholar 

  • Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA (2009) The Rap80–BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci USA 106:3166–3171

    PubMed  CAS  Google Scholar 

  • Sharma GG, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N, Bhadra U, Pandita RK, Porteus MH, Chen DJ, Cote J, Pandita TK (2010) MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol Cell Biol 30:3582–3595

    PubMed  CAS  Google Scholar 

  • Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M (2004) Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr Biol 14:1703–1711

    PubMed  CAS  Google Scholar 

  • Simons J (1995) Genetic, epigenetic, dysgenetic, and non-genetic mechanisms in tumorigenesis. Crit Rev Oncog 6:261–273

    PubMed  CAS  Google Scholar 

  • Smallwood A, Esteve PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 10:1169–1178

    Google Scholar 

  • Smilenov LB, Hall EJ, Bonner WM, Sedelnikova OA (2006) A microbeam study of DNA double-strand breaks in bystander primary human fibroblasts. Radiat Prot Dosim 122:256–259

    CAS  Google Scholar 

  • Sokolov MV, Smilenov LB, Hall EJ, Panyutin IG, Bonner WM, Sedelnikova OA (2005) Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts. Oncogene 24:7257–7265

    PubMed  CAS  Google Scholar 

  • Sokolov MV, Dickey JS, Bonner WM, Sedelnikova OA (2007) gamma-H2AX in bystander cells—not just a radiation-triggered event, a cellular response to stress mediated by intercellular communication. Cell Cycle 6:2210–2212

    PubMed  CAS  Google Scholar 

  • Sonoda E, Hochegger H, Saberi A, Taniguchi Y, Takeda S (2006) Differential usage of non-homologous end-joining and homologous recombination in double strand break repair. DNA Repair 5:1021–1029

    PubMed  CAS  Google Scholar 

  • Spada F, Haemmer A, Kuch D, Rothbauer U, Schermelleh L, Kremmer E, Carell T, Längst G, Leonhardt H (2007) DNMT1 but not its interaction with the replication machinery is required for maintenance of DNA methylation in human cells. J Cell Biol 176:565–571

    PubMed  CAS  Google Scholar 

  • Spagnolo L, Rivera-Calzada A, Pearl LH, Llorca O (2006) Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol Cell 22:511–519

    PubMed  CAS  Google Scholar 

  • Stackhouse M, Bedford J (1993) An ionizing radiation-sensitive mutant of CHO cells: irs-20. II. Dose-rate effects and cellular recovery processes. Radiat Res 136:250–4

    PubMed  CAS  Google Scholar 

  • Steel GG (1996) From targets to genes: a brief history of radiosensitivity. Phys Med Biol 41:205–222

    PubMed  CAS  Google Scholar 

  • Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D (2009) The RIDDLE syndrome protein mediates a ubiquitin-dependent signalling cascade at sites of DNA damage. Cell 136:420–434

    PubMed  CAS  Google Scholar 

  • Stiff T, O’Driscoll M, Rief N, Iwabuchi K, Lobrich M, Jeggo PA (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64:2390–2396

    PubMed  CAS  Google Scholar 

  • Strom L, Lindroos HB, Shirahige K, Sjogren C (2004) Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair. Mol Cell 16:1003–1015

    PubMed  Google Scholar 

  • Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP (2005) MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123:1213–1226

    PubMed  CAS  Google Scholar 

  • Sun ZW, Allis CD (2002) Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418:104–108

    PubMed  CAS  Google Scholar 

  • Sun Y, Jiang X, Chen S, Fernandes N, Price BD (2005) A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci USA 102:13182–13187

    PubMed  CAS  Google Scholar 

  • Sun Y, Xu Y, Roy K, Price BD (2007) DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol 27:8502–8509

    PubMed  CAS  Google Scholar 

  • Sun Y, Jiang X, Xu Y, Ayrapetov MK, Moreau LA, Whetstine JR, Price BD (2009) Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol 11:1376–1382

    PubMed  CAS  Google Scholar 

  • Suzuki M, Suzuki K, Kodama S, Watanabe M (2006) Phosphorylated histone H2AX foci persist on rejoined mitotic chromosomes in normal human diploid cells exposed to ionizing radiation. Radiat Res 165:269–276

    PubMed  CAS  Google Scholar 

  • Svotelis A, Gévry N, Grondin G, Gaundreau L (2010) H2A.Z overexpression promotes cellular proliferation of breast cancer cells. Cell Cycle 9:364–370

    PubMed  CAS  Google Scholar 

  • Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y (2004) Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116:51–61

    PubMed  CAS  Google Scholar 

  • Taipale M, Rea S, Richter K, Vilar A, Lichter P, Imhof A, Akhtar A (2005) hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol Cell Biol 25:6798–6810

    PubMed  CAS  Google Scholar 

  • Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14:1025–1040

    PubMed  CAS  Google Scholar 

  • Thakar A, Gupta P, Ishibashi T, Finn R, Silva-Moreno B, Uchiyama S, Fukui K, Tomschik M, Ausio J, Zlatanova J (2009) H2A.Z and H3.3 histone variants affect nucleosome structure: biochemical and biophysical studies. Biochemistry 48(46):10852–10857; Nov 24

    Google Scholar 

  • Thaminy S, Newcomb B, Kim J, Gatbonton T, Foss E, Simon J, Bedalov A (2007) HST3 is regulated by MEC1-dependent proteolysis and controls the S phase checkpoint and sister chromatid cohesion by deacetylating histone H3 at lysine 56. J Biol Chem 282:3705–3714

    Google Scholar 

  • Tjeertes JV, Miller KM, Jackson SP (2009) Screen for DNA-damage responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J 28:1878–1889

    PubMed  CAS  Google Scholar 

  • Unal E, Arbel-Eden A, Sattler U, Schroff R, Lichten M, Haber JE, Koshland D (2004) DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol Cell 16:991–1002

    PubMed  Google Scholar 

  • van Attikum H, Gasser SM (2009) Crosstalk between histone modifications during the DNA damage response. Trends Cell Biol 19:207–217

    PubMed  Google Scholar 

  • van der Heijden GW, Derijck AAHA, Posfai E, Giele M, Pelczar P, Ramos L, Wansink DG, van der Vlag J, Peters AHFM, de Boer P (2007) Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation. Nat Genet 39:251–258

    PubMed  Google Scholar 

  • Van Heemst D, Brugmans L, Verkaik NS, van Gent DC (2004) End-joining of blunt DNA double-strand breaks in mammalian fibroblasts is precise and requires DNA-PK and XRCC4. DNA Repair Amst 3:43–50

    PubMed  Google Scholar 

  • Varga T, Aplan PD (2005) Chromosomal aberrations induced by double strand DNA breaks. DNA Repair Amst 4:1038–1046

    PubMed  CAS  Google Scholar 

  • Vempati RK, Jayani RS, Notani D, Sengupta A, Galande S, Haldar D (2010) p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals. J Biol Chem 285:28553–28564

    PubMed  CAS  Google Scholar 

  • Viens A, Mechold U, Brouillard F, Gilbert C, Leclerc P, Ogryzko V (2006) Analysis of human histone H2AZ deposition in vivo argues against its direct role in epigenetic templating mechanisms. Mol Cell Biol 26:5325–5335

    PubMed  CAS  Google Scholar 

  • Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Lamnoit Y, Fuks F (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874

    PubMed  CAS  Google Scholar 

  • Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP (1999) Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet 23:62–66

    PubMed  CAS  Google Scholar 

  • Wang B, Elledge SJ (2007) Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA 104:20759–20763

    PubMed  CAS  Google Scholar 

  • Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, Elledge SJ (2007) Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316:1194–1198

    PubMed  CAS  Google Scholar 

  • Ward IM, Chen J (2001) Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem 276:47759–47762

    PubMed  CAS  Google Scholar 

  • Watson GE, Lorimore SA, Macdonald DA, Wright EG (2000) Chromosomal instability in unirradiated cells induced in vivo by a bystander effect of ionizing radiation. Cancer Res 60:5608–5611

    PubMed  CAS  Google Scholar 

  • Willers H, Dahm-Daphi J, Powell SN (2004) Repair of radiation damage to DNA. Br J Cancer 90:1297–1301

    PubMed  CAS  Google Scholar 

  • Xu GL, Bestor TH, Bourch’his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Péquignot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402:187–191

    PubMed  CAS  Google Scholar 

  • Yamashita K, Shinohara M, Shinohara A (2004) Rad6-Bre1-mediated histone H2B ubiquitylation modulates the formation of double-strand breaks during meiosis. Proc Natl Acad Sci USA 101:11380–11385

    PubMed  CAS  Google Scholar 

  • Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449:478–482

    PubMed  CAS  Google Scholar 

  • Yang H, Pesavento JJ, Starnes TW, Cryderman DE, Wallrath LL, Kelleher NL, Mizzen CA (2008) Preferential dimethylation of histone H4 lysine 20 by suv4-20. J Biol Chem 283:12085–12092

    PubMed  CAS  Google Scholar 

  • Yano K, Morotomi-Yano K, Wang SY, Uematsu N, Lee KJ, Asaithamby A, Weterings E, Chen DJ (2008) Ku recruits XLF to DNA double-strand breaks. EMBO Rep 9:91–96

    PubMed  CAS  Google Scholar 

  • Yasui DH, Peddada S, Bieda MC, Vallero RO, Hogart A, Nagarajan RP, Thatcher KN, Farnham PJ, LaSalle JM (2007) Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci USA 104:19416–19421

    PubMed  CAS  Google Scholar 

  • Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340

    PubMed  CAS  Google Scholar 

  • Yu F, Zingler N, Schumann G, Strätling WH (2001) Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription. Nucleic Acids Res 29:4493–4501

    PubMed  CAS  Google Scholar 

  • Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F (2004) Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol 24:708–718

    PubMed  CAS  Google Scholar 

  • Zhao XD, Han X, Chew JL, Liu J, Chiu KP, Choo A, Orlov YL, Sung W-K, Shahab A, Kuznetsov VA, Bourque G, Oh S, Ruan Y, Ng H-H, Wei C-L (2007a) Whole-genome mapping of histone H3Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1:286–298

    PubMed  CAS  Google Scholar 

  • Zhao GY, Sonoda E, Barber LJ, Oka H, Murakawa Y, Yamada K, Ikura T, Wang X, Kobayashi M, Yamamoto K, Boulton SJ, Takeda S (2007b) A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Mol Cell 25:663–675

    PubMed  CAS  Google Scholar 

  • Zhou H, Randers-Pehrson G, Waldren CA, Vannais D, Hall EJ, Hei TK (2000) Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc Natl Acad Sci USA 97:2099–2104

    PubMed  CAS  Google Scholar 

  • Zhou H, Ivanov VN, Gillespie J, Geard CR, Amundson SA, Brenner DJ, Yu Z, Lieberman HB, Hei TK (2005) Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signalling pathway. Proc Natl Acad Sci USA 102:14641–14646

    PubMed  CAS  Google Scholar 

  • Zlatanova J, Thakar A (2008) H2A.Z: view from the top. Structure 16:166–179

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The support of the Australian Institute of Nuclear Science and Engineering is acknowledged. TCK was the recipient of AINSE awards. Epigenomic Medicine Lab is supported by the National Health and Medical Research Council of Australia (566559). This work is funded by the CRC for Biomedical Imaging Development Ltd, established and supported under the Australian Government’s Cooperative Research Centres (CRC) program. CO and LM are supported by Melbourne Research (University of Melbourne) and Australian Postgraduate Awards, respectively, and Biomedical Imaging CRC supplementary scholarships.

Author information

Authors and Affiliations

  1. Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, 75 Commercial Road, Melbourne, Victoria, Australia

    Christian Orlowski, Li-Jeen Mah, Raja S. Vasireddy & Tom C. Karagiannis

  2. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia

    Christian Orlowski, Li-Jeen Mah, Raja S. Vasireddy, Assam El-Osta & Tom C. Karagiannis

  3. Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia

    Christian Orlowski, Raja S. Vasireddy & Assam El-Osta

  4. Faculty of Medicine, Monash University, Melbourne, Victoria, Australia

    Assam El-Osta

Authors
  1. Christian Orlowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-Jeen Mah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raja S. Vasireddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Assam El-Osta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tom C. Karagiannis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tom C. Karagiannis.

Additional information

Communicated by J. Karlseder

Christian Orlowski and Li-Jeen Mah contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Orlowski, C., Mah, LJ., Vasireddy, R.S. et al. Double-strand breaks and the concept of short- and long-term epigenetic memory. Chromosoma 120, 129–149 (2011). https://doi.org/10.1007/s00412-010-0305-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00412-010-0305-6

Keywords

Search

Navigation