Epigenetic Modifications in Double-Strand Break DNA Damage Signaling and Repair

Factors involved in the cellular response to double-strand break (DSB) DNA damage have been identified as potential therapeutic targets that would greatly sensitize cancer cells to radiotherapy and genotoxic chemotherapy. These targets could disable the repair machinery and/or reinstate normal cell-cycle checkpoint leading to growth arrest, senescence, and apoptosis. It is now clear that a major aspect of the DNA damage response occurs through specific interactions with chromatin structure and its modulation. It implicates highly dynamic posttranslational modifications of histones that are critical for DNA damage recognition and/or signaling, repair of the lesion, and release of cell-cycle arrest. Therefore, drugs that target the enzymes responsible for these modifications, or the protein modules reading them, have very high therapeutic potential. This review presents the current state of knowledge on the different chromatin modifications and their roles in each step of eukaryotic DSB DNA damage response. Clin Cancer Res; 16(18); 4543–52. ©2010 AACR.

[1]  R. Medema,et al.  Wip1 phosphatase is associated with chromatin and dephosphorylates γH2AX to promote checkpoint inhibition , 2010, Oncogene.

[2]  S. Elledge,et al.  Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage , 2007, Proceedings of the National Academy of Sciences.

[3]  F. Thoma,et al.  Contribution of the Serine 129 of Histone H2A to Chromatin Structure , 2007, Molecular and Cellular Biology.

[4]  E. Rogakou,et al.  Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo , 1999, The Journal of cell biology.

[5]  R. Plummer.  Perspective on the Pipeline of Drugs Being Developed with Modulation of DNA Damage as a Target , 2010, Clinical Cancer Research.

[6]  S. Jackson,et al.  Screen for DNA-damage-responsive histone modifications identifies H 3 K 9 Ac and H 3 K 56 Ac in human cells , 2009 .

[7]  D. Koshland,et al.  Distinct targets of the Eco1 acetyltransferase modulate cohesion in S phase and in response to DNA damage. , 2009, Molecular cell.

[8]  J. Boeke,et al.  The Sirtuins Hst3 and Hst4p Preserve Genome Integrity by Controlling Histone H3 Lysine 56 Deacetylation , 2006, Current Biology.

[9]  J. O’Shaughnessy,et al.  ADP-Ribose ) Polymerase as a Novel Therapeutic get in Cancer , 2010 .

[10]  Jeffrey G. Linger,et al.  Acetylated Lysine 56 on Histone H3 Drives Chromatin Assembly after Repair and Signals for the Completion of Repair , 2008, Cell.

[11]  R. Bonner,et al.  Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks , 2003, Nature Cell Biology.

[12]  Xingzhi Xu,et al.  Protein Phosphatase 6 Interacts with the DNA-Dependent Protein Kinase Catalytic Subunit and Dephosphorylates γ-H2AX , 2010, Molecular and Cellular Biology.

[13]  M. Osley,et al.  Chromatin remodelling at a DNA double-strand break site in Saccharomyces cerevisiae , 2005, Nature.

[14]  Sang Eun Lee,et al.  The Yeast Chromatin Remodeler RSC Complex Facilitates End Joining Repair of DNA Double-Strand Breaks , 2005, Molecular and Cellular Biology.

[15]  Christopher K. Glass,et al.  Tyrosine Dephosphorylation of H2AX Modulates Apoptosis and Survival Decisions , 2009, Nature.

[16]  T. Ono,et al.  Histone acetyltransferase 1 is dispensable for replication-coupled chromatin assembly but contributes to recover DNA damages created following replication blockage in vertebrate cells. , 2006, Biochemical and biophysical research communications.

[17]  M. Shipp,et al.  BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. , 2009, Molecular cell.

[18]  Kirk C. Hansen,et al.  CBP / p300-mediated acetylation of histone H3 on lysine 56 , 2009, Nature.

[19]  Pierre-Étienne Jacques,et al.  Systematic identification of fragile sites via genome-wide location analysis of γ-H2AX , 2010, Nature Structural &Molecular Biology.

[20]  S. Jentsch,et al.  Chromosome-wide Rad51 spreading and SUMO-H2A.Z-dependent chromosome fixation in response to a persistent DNA double-strand break. , 2009, Molecular cell.

[21]  H. Kimura,et al.  DNA Damage-Dependent Acetylation and Ubiquitination of H2AX Enhances Chromatin Dynamics , 2007, Molecular and Cellular Biology.

[22]  J. Tyler,et al.  Chaperoning Histones during DNA Replication and Repair , 2010, Cell.

[23]  Jung-Ae Kim,et al.  Heterochromatin is refractory to γ-H2AX modification in yeast and mammals , 2007, The Journal of cell biology.

[24]  So-jung Kim,et al.  A cooperative activation loop among SWI/SNF, γ‐H2AX and H3 acetylation for DNA double‐strand break repair , 2010, The EMBO journal.

[25]  James H. Doroshow,et al.  Histone γH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers , 2010, Clinical Cancer Research.

[26]  S. Gasser,et al.  Crosstalk between histone modifications during the DNA damage response. , 2009, Trends in cell biology.

[27]  Laurence Pelletier,et al.  Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin Ligase , 2007, Science.

[28]  T. Ludwig,et al.  Involvement of Human MOF in ATM Function , 2005, Molecular and Cellular Biology.

[29]  B. Kim,et al.  Cohesion establishment factor, Eco1 represses transcription via association with histone demethylase, LSD1. , 2010, Biochemical and biophysical research communications.

[30]  Jacques Côté,et al.  The diverse functions of histone acetyltransferase complexes. , 2003, Trends in genetics : TIG.

[31]  Wei-Hua Wu,et al.  ATP-Driven Exchange of Histone H2AZ Variant Catalyzed by SWR1 Chromatin Remodeling Complex , 2004, Science.

[32]  Jung-Ae Kim,et al.  Chromatin assembly factors Asf1 and CAF-1 have overlapping roles in deactivating the DNA damage checkpoint when DNA repair is complete , 2009, Proceedings of the National Academy of Sciences.

[33]  M. Esteller.  Cancer epigenomics: DNA methylomes and histone-modification maps , 2007, Nature Reviews Genetics.

[34]  B. Cairns,et al.  Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA double-strand break repair. , 2005, Genes & development.

[35]  Y. Doyon,et al.  Eaf1 Is the Platform for NuA4 Molecular Assembly That Evolutionarily Links Chromatin Acetylation to ATP-Dependent Exchange of Histone H2A Variants , 2008, Molecular and Cellular Biology.

[36]  Jiri Bartek,et al.  Mdc1 couples DNA double‐strand break recognition by Nbs1 with its H2AX‐dependent chromatin retention , 2004, The EMBO journal.

[37]  R. Wysocki,et al.  Yeast G1 DNA damage checkpoint regulation by H2A phosphorylation is independent of chromatin remodeling , 2006, Proceedings of the National Academy of Sciences.

[38]  S. Kron,et al.  Dissection of Rad9 BRCT domain function in the mitotic checkpoint response to telomere uncapping. , 2009, DNA repair.

[39]  Yu Zhang,et al.  RSC Mobilizes Nucleosomes To Improve Accessibility of Repair Machinery to the Damaged Chromatin , 2006, Molecular and Cellular Biology.

[40]  Michael A. Freitas,et al.  Histone H4 lysine 91 acetylation a core domain modification associated with chromatin assembly. , 2005, Molecular cell.

[41]  J. Tyler,et al.  Localized Histone Acetylation and Deacetylation Triggered by the Homologous Recombination Pathway of Double-Strand DNA Repair , 2005, Molecular and Cellular Biology.

[42]  Anindya Dutta,et al.  Human Rvb1/Tip49 Is Required for the Histone Acetyltransferase Activity of Tip60/NuA4 and for the Downregulation of Phosphorylation on H2AX after DNA Damage , 2008, Molecular and Cellular Biology.

[43]  James G. McNally,et al.  Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks , 2006, The Journal of cell biology.

[44]  K. Nephew,et al.  New anti-cancer strategies: epigenetic therapies and biomarkers. , 2005, Frontiers in bioscience : a journal and virtual library.

[45]  Grant W. Brown,et al.  Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map , 2007, Nature.

[46]  T. Krude,et al.  Induction of CAF-1 Expression in Response to DNA Strand Breaks in Quiescent Human Cells , 2006, Molecular and Cellular Biology.

[47]  J. Hayes,et al.  Chromatin in need of a fix: phosphorylation of H2AX connects chromatin to DNA repair. , 2005, Molecular cell.

[48]  V. Yamazaki,et al.  A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage , 2000, Current Biology.

[49]  Sung-Hee Ahn,et al.  Phosphorylation of Histone H4 Serine 1 during DNA Damage Requires Casein Kinase II in S. cerevisiae , 2005, Current Biology.

[50]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[51]  J. O’Shaughnessy,et al.  Poly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer , 2010, Clinical Cancer Research.

[52]  A. El-Osta,et al.  γH2AX: a sensitive molecular marker of DNA damage and repair , 2010, Leukemia.

[53]  Nancy L. Maas,et al.  Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3 and Hst4. , 2006, Molecular cell.

[54]  J. Côté,et al.  Regulation of NuA4 Histone Acetyltransferase Activity in Transcription and DNA Repair by Phosphorylation of Histone H4 , 2005, Molecular and Cellular Biology.

[55]  P. Grandi,et al.  A CAF-1–PCNA-Mediated Chromatin Assembly Pathway Triggered by Sensing DNA Damage , 2000, Molecular and Cellular Biology.

[56]  Ali Jazayeri,et al.  Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Tilby,et al.  γH2AX Foci Form Preferentially in Euchromatin after Ionising-Radiation , 2007, PloS one.

[58]  S. Jackson,et al.  Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. , 2004, Molecular cell.

[59]  Katherine S. Yang-Iott,et al.  Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin. , 2009, Molecular cell.

[60]  Paul Tempst,et al.  WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase , 2009 .

[61]  Makoto Nakanishi,et al.  Chk1 Is a Histone H3 Threonine 11 Kinase that Regulates DNA Damage-Induced Transcriptional Repression , 2008, Cell.

[62]  David J. Chen,et al.  MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair , 2010, Molecular and Cellular Biology.

[63]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[64]  Michael A. Freitas,et al.  Histone H3-K56 acetylation is catalyzed by histone chaperone-dependent complexes. , 2007, Molecular cell.

[65]  N. Krogan,et al.  INO80 and γ-H2AX Interaction Links ATP-Dependent Chromatin Remodeling to DNA Damage Repair , 2004, Cell.

[66]  John R Yates,et al.  Acetylation by Tip60 Is Required for Selective Histone Variant Exchange at DNA Lesions , 2004, Science.

[67]  Luc Gaudreau,et al.  NuA4-dependent Acetylation of Nucleosomal Histones H4 and H2A Directly Stimulates Incorporation of H2A.Z by the SWR1 Complex* , 2010, The Journal of Biological Chemistry.

[68]  K. Ratnakumar,et al.  RSC Functions as an Early Double-Strand-Break Sensor in the Cell's Response to DNA Damage , 2007, Current Biology.

[69]  P. Russell,et al.  Cooperative Control of Crb2 by ATM Family and Cdc2 Kinases Is Essential for the DNA Damage Checkpoint in Fission Yeast , 2005, Molecular and Cellular Biology.

[70]  Michael Lichten,et al.  Distribution and Dynamics of Chromatin Modification Induced by a Defined DNA Double-Strand Break , 2004, Current Biology.

[71]  J. Côté,et al.  Histone modifications in response to DNA damage. , 2007, Mutation research.

[72]  T. Hughes,et al.  Regulation of chromosome stability by the histone H2A variant Htz1, the Swr1 chromatin remodeling complex, and the histone acetyltransferase NuA4. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[73]  J. Mata,et al.  Methylation of Histone H4 Lysine 20 Controls Recruitment of Crb2 to Sites of DNA Damage , 2004, Cell.

[74]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[75]  D. Cortez,et al.  Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. , 2008, Molecular cell.

[76]  Junhong Han,et al.  Rtt109 Acetylates Histone H3 Lysine 56 and Functions in DNA Replication , 2007, Science.

[77]  Georges Mer,et al.  Structural Basis for the Methylation State-Specific Recognition of Histone H4-K20 by 53BP1 and Crb2 in DNA Repair , 2006, Cell.

[78]  Z. Herceg,et al.  Histone acetylation by Trrap–Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks , 2006, Nature Cell Biology.

[79]  J. Lieberman,et al.  A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery , 2006, Nature.

[80]  Robert Driscoll,et al.  Yeast Rtt109 Promotes Genome Stability by Acetylating Histone H3 on Lysine 56 , 2007, Science.

[81]  F. Alt,et al.  Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[82]  M. Parthun,et al.  Histone H3 and the Histone Acetyltransferase Hat1p Contribute to DNA Double-Strand Break Repair , 2002, Molecular and Cellular Biology.

[83]  S. Gasser,et al.  Distinct roles for SWR1 and INO80 chromatin remodeling complexes at chromosomal double‐strand breaks , 2007, The EMBO journal.

[84]  Junjie Chen,et al.  Histone H2AX Is Phosphorylated in an ATR-dependent Manner in Response to Replicational Stress* , 2001, The Journal of Biological Chemistry.

[85]  C. Peterson,et al.  Cellular machineries for chromosomal DNA repair. , 2004, Genes & development.

[86]  Imen Lassadi,et al.  High‐resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome , 2010, The EMBO journal.

[87]  Xiao-dan Liu,et al.  DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylation in response to DNA damage and cell cycle progression , 2010, BMC Molecular Biology.

[88]  Michel C. Nussenzweig,et al.  Genomic Instability in Mice Lacking Histone H2AX , 2002, Science.

[89]  T. Paull,et al.  Activation and regulation of ATM kinase activity in response to DNA double-strand breaks , 2007, Oncogene.

[90]  Michael B. Yaffe,et al.  RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly , 2007, Cell.

[91]  N. Mailand,et al.  Nucleotide excision repair–induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response , 2009, The Journal of cell biology.

[92]  N. Van Larebeke,et al.  Endogenous DNA damage in humans: a review of quantitative data. , 2004, Mutagenesis.

[93]  Bruce Stillman,et al.  Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase , 1998, Current Biology.

[94]  Xiaofeng Jiang,et al.  A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[95]  A. Gingras,et al.  PP4 is a γH2AX phosphatase required for recovery from the DNA damage checkpoint , 2008, EMBO reports.

[96]  Oscar Fernandez-Capetillo,et al.  Phosphorylation of Histone H2B at DNA Double-Strand Breaks , 2004, The Journal of experimental medicine.

[97]  R. Greenberg,et al.  ATM-Dependent Chromatin Changes Silence Transcription In cis to DNA Double-Strand Breaks , 2010, Cell.

[98]  Michael Lichten,et al.  DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. , 2004, Molecular cell.

[99]  Andrew J Link,et al.  A Protein Complex Containing the Conserved Swi2/Snf2-Related ATPase Swr1p Deposits Histone Variant H2A.Z into Euchromatin , 2004, PLoS biology.

[100]  G. Almouzni,et al.  Local action of the chromatin assembly factor CAF‐1 at sites of nucleotide excision repair in vivo , 2003, The EMBO journal.

[101]  J. Lieberman,et al.  A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication. , 2008, Molecular cell.

[102]  David Hawke,et al.  A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response , 2005, Nature.

[103]  S. Jackson,et al.  Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells , 2009, The EMBO journal.

[104]  A. Imbalzano,et al.  Mammalian SWI/SNF complexes facilitate DNA double‐strand break repair by promoting γ‐H2AX induction , 2006, The EMBO journal.

[105]  Robert Wysocki,et al.  Role of Dot1-Dependent Histone H3 Methylation in G1 and S Phase DNA Damage Checkpoint Functions of Rad9 , 2005, Molecular and Cellular Biology.

[106]  Alexander W. Bird,et al.  Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair , 2002, Nature.

[107]  Jiri Bartek,et al.  RNF8 Ubiquitylates Histones at DNA Double-Strand Breaks and Promotes Assembly of Repair Proteins , 2007, Cell.

[108]  Stephen P. Jackson,et al.  A role for Saccharomyces cerevisiae histone H2A in DNA repair , 2000, Nature.

[109]  M. Yaffe,et al.  MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks , 2008, Cell.

[110]  I. Dobbie,et al.  Histone H2A phosphorylation and H3 methylation are required for a novel Rad9 DSB repair function following checkpoint activation. , 2006, DNA repair.

[111]  J. Lieberman,et al.  γ-H2AX Dephosphorylation by Protein Phosphatase 2A Facilitates DNA Double-Strand Break Repair , 2005 .

[112]  R. Bristow,et al.  “Contextual” Synthetic Lethality and/or Loss of Heterozygosity: Tumor Hypoxia and Modification of DNA Repair , 2010, Clinical Cancer Research.

[113]  G. Wani,et al.  Chromatin restoration following nucleotide excision repair involves the incorporation of ubiquitinated H2A at damaged genomic sites. , 2009, DNA repair.

[114]  J. Neefjes,et al.  DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A. , 2006, Genes & development.

[115]  Jef D. Boeke,et al.  Insights into the Role of Histone H3 and Histone H4 Core Modifiable Residues in Saccharomyces cerevisiae , 2005, Molecular and Cellular Biology.

[116]  P. Jeggo,et al.  ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation , 2004, Cancer Research.

[117]  C. Peterson,et al.  Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptation in response to DNA damage. , 2006, Genes & development.

[118]  F. Alt,et al.  MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. , 2006, Molecular cell.

[119]  Barbara Hohn,et al.  Recruitment of the INO80 Complex by H2A Phosphorylation Links ATP-Dependent Chromatin Remodeling with DNA Double-Strand Break Repair , 2004, Cell.

[120]  S. Jackson,et al.  Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks , 2009, Nature.

[121]  G. Almouzni,et al.  New Histone Incorporation Marks Sites of UV Repair in Human Cells , 2006, Cell.

[122]  Aedín C Culhane,et al.  RAP80 Targets BRCA1 to Specific Ubiquitin Structures at DNA Damage Sites , 2007, Science.