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Cell Research
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Regulation of DNA double-strand break repair pathway choice

Cell Researchvolume 18, pages134–147 (2008)Cite this article

Abstract

DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including large- or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR), and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1(XRS2) complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.

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References

  1. Shen Z, Nickoloff JA . Mammalian homologous recombination repair and cancer intervention. In: Wei Q, Li L, Chen DJ, eds. DNA Repair, Genetic Instability, and Cancer. Singapore: World Scientific Publishing Co., 2007:119–156.

    Chapter  Google Scholar 

  2. Paques F, Haber JE . Multiple pathways of recombination induced by double-strand breaks inSaccharomyces cerevisiae.Microbiol Mol Biol Rev 1999;63:349–404.

    CAS PubMed PubMed Central  Google Scholar 

  3. Franco S, Alt FW, Manis JP . Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations.DNA Repair (Amst) 2006;5:1030–1041.

    Article CAS  Google Scholar 

  4. Chaudhuri J, Basu U, Zarrin A,et al. Evolution of the immunoglobulin heavy chain class switch recombination mechanism.Adv Immunol 2007;94:157–214.

    Article CAS PubMed  Google Scholar 

  5. Keeney S, Neale MJ . Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation.Biochem Soc Trans 2006;34:523–525.

    Article CAS PubMed  Google Scholar 

  6. Murnane JP . Telomeres and chromosome instability.DNA Repair (Amst) 2006;5:1082–1092.

    Article CAS  Google Scholar 

  7. Acilan C, Potter DM, Saunders WS . DNA repair pathways involved in anaphase bridge formation.Genes Chromosomes Cancer 2007;46:522–531.

    Article CAS PubMed  Google Scholar 

  8. Ward J . The nature of lesions formed by ionizing radiation. In: Nickoloff JA, Hoekstra MF, eds. DNA Damage and Repair: DNA Repair in Higher Eukaryotes. Totowa, NJ: Humana Press, 1998:65–84.

    Google Scholar 

  9. Limoli CL, Giedzinski E, Bonner WM, Cleaver JE . UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, γ-H2AX formation, and Mre11 relocalization.Proc Natl Acad Sci USA 2002;99:233–238.

    Article CAS PubMed  Google Scholar 

  10. Bosco EE, Mayhew CN, Hennigan RF,et al. RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult.Nucleic Acids Res 2004;32:25–34.

    Article CAS PubMed PubMed Central  Google Scholar 

  11. Degrassi F, Fiore M, Palitti F . Chromosomal aberrations and genomic instability induced by topoisomerase-targeted antitumour drugs.Curr Med Chem Anticancer Agents 2004;4:317–325.

    Article CAS PubMed  Google Scholar 

  12. Su TT . Cellular responses to DNA damage: one signal, multiple choices.Annu Rev Genet 2006;40:187–208.

    Article CAS PubMed  Google Scholar 

  13. Rothstein R, Michel B, Gangloff S . Replication fork pausing and recombination or “gimme a break”.Genes Dev 2000;14:1–10.

    CAS PubMed  Google Scholar 

  14. Clikeman JA, Khalsa GJ, Barton SL, Nickoloff JA . Homologous recombinational repair of double-strand breaks in yeast is enhanced byMAT heterozygosity through yKu-dependent and -independent mechanisms.Genetics 2001;157:579–589.

    CAS PubMed PubMed Central  Google Scholar 

  15. Lin Y, Lukacsovich T, Waldman AS . Multiple pathways for repair of double-strand breaks in mammalian chromosomes.Mol Cell Biol 1999;19:8353–8360.

    Article CAS PubMed PubMed Central  Google Scholar 

  16. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ . ATM phosphorylates histone H2AX in response to DNA double-strand breaks.J Biol Chem 2001;276:42462–42467.

    Article CAS PubMed  Google Scholar 

  17. Collis SJ, DeWeese TL, Jeggo PA, Parker AR . The life and death of DNA-PK.Oncogene 2005;24:949–961.

    Article CAS PubMed  Google Scholar 

  18. Cui X, Yu Y, Gupta S,et al. Autophosphorylation of DNA-dependent protein kinase regulates DNA end processing and may also alter double-strand break repair pathway choice.Mol Cell Biol 2005;25:10842–10852.

    Article CAS PubMed PubMed Central  Google Scholar 

  19. Shao RG, Cao CX, Zhang H,et al. Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes.EMBO J 1999;18:1397–1406.

    Article CAS PubMed PubMed Central  Google Scholar 

  20. Burma S, Chen DJ . Role of DNA-PK in the cellular response to DNA double-strand breaks.DNA Repair (Amst) 2004;3:909–918.

    Article CAS  Google Scholar 

  21. Chan DW, Ye RQ, Veillette CJ, Lees-Miller SP . DNA-dependent protein kinase phosphorylation sites in Ku 70/80 heterodimer.Biochemistry 1999;38:1819–1828.

    Article CAS PubMed  Google Scholar 

  22. Karmakar P, Piotrowski J, Brosh RM,et al. Werner protein is a target of DNA-dependent protein kinasein vivo andin vitro, and its catalytic activities are regulated by phosphorylation.J Biol Chem 2002;277:18291–18302.

    Article CAS PubMed  Google Scholar 

  23. Yannone SM, Roy S, Chan DW,et al. Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase.J Biol Chem 2001;276:38242–38248.

    CAS PubMed  Google Scholar 

  24. Stucki M, Jackson SP . γH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes.DNA Repair (Amst) 2006;5:534–543.

    Article CAS  Google Scholar 

  25. Riballo E, Kuhne M, Rief N,et al. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to γ-H2AX foci.Mol Cell 2004;16:715–724.

    Article CAS PubMed  Google Scholar 

  26. Jeggo PA, O'Neill P . The Greek goddess, Artemis, reveals the secrets of her cleavage.DNA Repair (Amst) 2002;1:771–777.

    Article CAS  Google Scholar 

  27. Nick McElhinny SA, Havener JM, Garcia-Diaz M,et al. A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining.Mol Cell 2005;19:357–366.

    Article CAS PubMed  Google Scholar 

  28. Durant ST, Nickoloff JA . Good timing in the cell cycle for precise DNA repair by BRCA1.Cell Cycle 2005;4:1216–1222.

    Article CAS PubMed  Google Scholar 

  29. Huang TT, D'Andrea AD . Regulation of DNA repair by ubiquitylation.Nat Rev Mol Cell Biol 2006;7:323–334.

    Article CAS PubMed  Google Scholar 

  30. Wang M, Wu W, Wu W,et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways.Nucleic Acids Res 2006;34:6170–6182.

    Article CAS PubMed PubMed Central  Google Scholar 

  31. Daley JM, Palmbos PL, Wu D, Wilson TE . Nonhomologous end joining in yeast.Annu Rev Genet 2005;39:431–451.

    Article CAS PubMed  Google Scholar 

  32. Lees-Miller SP, Meek K . Repair of DNA double strand breaks by non-homologous end joining.Biochimie 2003;85:1161–1173.

    Article CAS PubMed  Google Scholar 

  33. Burma S, Chen BP, Chen DJ . Role of non-homologous end joining (NHEJ) in maintaining genomic integrity.DNA Repair (Amst) 2006;5:1042–1048.

    Article CAS  Google Scholar 

  34. Rouse J, Jackson SP . Interfaces between the detection, signaling, and repair of DNA damage.Science 2002;297:547–551.

    Article CAS PubMed  Google Scholar 

  35. Strathern JN, Shafer BK, McGill CB . DNA synthesis errors associated with double-strand break repair.Genetics 1995;140:965–972.

    CAS PubMed PubMed Central  Google Scholar 

  36. Nickoloff JA . Recombination: mechanisms and roles in tumorigenesis. In: Bertino JR, ed. Encyclopedia of Cancer. 2nd Edition. San Diego, USA: Elsevier Science, 2002:49–59.

    Chapter  Google Scholar 

  37. Krogh BO, Symington LS . Recombination proteins in yeast.Annu Rev Genet 2004;38:233–271.

    Article CAS PubMed  Google Scholar 

  38. West SC . Molecular views of recombination proteins and their control.Nat Rev Mol Cell Biol 2003;4:435–445.

    Article CAS PubMed  Google Scholar 

  39. Champion MD, Hawley RS . Playing for half the deck: the molecular biology of meiosis.Nat Cell Biol 2002;4(Suppl):s50–s56.

    Article PubMed  Google Scholar 

  40. Myung K, Datta A, Chen C, Kolodner RD . SGS1, theSaccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination.Nat Genet 2001;27:113–116.

    Article CAS PubMed  Google Scholar 

  41. Cheok CF, Bachrati CZ, Chan KL,et al. Roles of the Bloom's syndrome helicase in the maintenance of genome stability.Biochem Soc Trans 2005;33:1456–1459.

    Article CAS PubMed  Google Scholar 

  42. Signon L, Malkova A, Naylor ML, Klein H, Haber JE . Genetic requirements for RAD51- and RAD54-independent break-induced replication repair of a chromosomal double-strand break.Mol Cell Biol 2001;21:2048–2056.

    Article CAS PubMed PubMed Central  Google Scholar 

  43. Krishna S, Wagener BM, Liu HP,et al. Mre11 and Ku regulation of double-strand break repair by gene conversion and break-induced replication.DNA Repair (Amst) 2007;6:797–808.

    Article CAS  Google Scholar 

  44. Dronkert MLG, Beverloo HB, Johnson RD,et al. MouseRAD54 affects DNA double-strand break repair and sister chromatid exchange.Mol Cell Biol 2000;20:3147–3156.

    Article CAS PubMed PubMed Central  Google Scholar 

  45. Essers J, Hendriks RW, Swagemakers SM,et al. Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination.Cell 1997;89:195–204.

    Article CAS PubMed  Google Scholar 

  46. Bezzubova O, Silbergleit A, Yamaguchi-Iwai Y, Takeda S, Buerstedde JM . Reduced X-ray resistance and homologous recombination frequencies in a RAD54−/− mutant of the chicken DT40 cell line.Cell 1997;89:185–193.

    Article CAS PubMed  Google Scholar 

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

    Article CAS  Google Scholar 

  48. Yang H, Jeffrey PD, Miller J,et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.Science 2002;297:1837–1848.

    Article CAS PubMed  Google Scholar 

  49. Zhang Y, Rowley JD . Chromatin structural elements and chromosomal translocations in leukemia.DNA Repair (Amst) 2006;5:1282–1297.

    Article CAS  Google Scholar 

  50. Karanjawala ZE, Grawunder U, Hsieh CL, Lieber MR . The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts.Curr Biol 1999;9:1501–1504.

    Article CAS PubMed  Google Scholar 

  51. Ferguson DO, Sekiguchi JM, Chang S,et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations.Proc Natl Acad Sci USA 2000;97:6630–6633.

    Article CAS PubMed PubMed Central  Google Scholar 

  52. Zha S, Alt FW, Cheng HL, Brush JW, Li G . Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells.Proc Natl Acad Sci USA 2007;104:4518–4523.

    Article CAS PubMed PubMed Central  Google Scholar 

  53. Sharpless NE, Ferguson DO, O'Hagan RC,et al. Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions.Mol Cell 2001;8:1187–1196.

    Article CAS PubMed  Google Scholar 

  54. Tong WM, Cortes U, Hande MP,et al. Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation.Cancer Res 2002;62:6990–6996.

    CAS PubMed  Google Scholar 

  55. Sugawara N, Haber JE . Characterization of double-strand break-induced recombination: homology requirements and single-stranded DNA formation.Mol Cell Biol 1992;12:563–575.

    Article CAS PubMed PubMed Central  Google Scholar 

  56. Lee SE, Moore JK, Holmes A,et al.Saccharomyces Ku70, Mre11/Rad50, and RPA proteins regulate adaptation to G2/M arrest after DNA damage.Cell 1998;94:399–409.

    Article CAS PubMed  Google Scholar 

  57. Bressan DA, Baxter BK, Petrini JHJ . The Mre11-Rad50-Xrs2 protein complex facilitates homologous recombination-based double-strand break repair inSaccharomyces cerevisiae.Mol Cell Biol 1999;19:7681–7687.

    Article CAS PubMed PubMed Central  Google Scholar 

  58. Moreau S, Ferguson JR, Symington LS . The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance.Mol Cell Biol 1999;19:556–566.

    Article CAS PubMed PubMed Central  Google Scholar 

  59. Ivanov EL, Sugawara N, White CI, Fabre F, Haber JE . Mutations inXRS2 andRAD50 delay but do not prevent mating-type switching inSaccharomyces cerevisiae.Mol Cell Biol 1994;14:3414–3425.

    Article CAS PubMed PubMed Central  Google Scholar 

  60. Milne GT, Jin S, Shannon KB, Weaver DT . Mutations in two Ku homologs define a DNA end-joining repair pathway inSaccharomyces cerevisiae.Mol Cell Biol 1996;16:4189–4198.

    Article CAS PubMed PubMed Central  Google Scholar 

  61. Moore JK, Haber JE . Cell-cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks inSaccharomyces cerevisiae.Mol Cell Biol 1996;16:2164–2173.

    Article CAS PubMed PubMed Central  Google Scholar 

  62. Kramer KM, Brock JA, Bloom K, Moore JK, Haber JE . Two different types of double-strand breaks inSaccharomyces cerevisiae are repaired by similarRAD52-independent, nonhomologous recombination events.Mol Cell Biol 1994;14:1293–1301.

    Article CAS PubMed PubMed Central  Google Scholar 

  63. Hammarsten O, DeFazio LG, Chu G . Activation of DNA-dependent protein kinase by single-stranded DNA ends.J Biol Chem 2000;275:1541–1550.

    Article CAS PubMed  Google Scholar 

  64. Budman J, Chu G . Processing of DNA for nonhomologous end-joining by cell-free extract.EMBO J 2005;24:849–860.

    Article CAS PubMed PubMed Central  Google Scholar 

  65. Boulton SJ . Cellular functions of the BRCA tumour-suppressor proteins.Biochem Soc Trans 2006;34:633–645.

    Article CAS PubMed  Google Scholar 

  66. Brenneman MA . BRCA1 and BRCA2 in DNA repair and genome stability. In: Nickoloff JA, Hoekstra MF, eds. DNA Damage and Repair, Vol 3: Advances from Phage to Humans. Totowa, NJ: Humana Press, 2001:237–267.

  67. Jung D, Giallourakis C, Mostoslavsky R, Alt FW . Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus.Annu Rev Immunol 2006;24:541–570.

    Article CAS PubMed  Google Scholar 

  68. Cremer T, Cremer M, Dietzel S,et al. Chromosome territories – a functional nuclear landscape.Curr Opin Cell Biol 2006;18:307–316.

    Article CAS PubMed  Google Scholar 

  69. Dekker J, Rippe K, Dekker M, Kleckner N . Capturing chromosome conformation.Science 2002;295:1306–1311.

    Article CAS PubMed  Google Scholar 

  70. Mortimer RK . Radiobiological and genetic studies on a polyploid series (haploid to hexaploid) ofSaccharomyces cerevisiae.Radiat Res 1958;9:312–326.

    Article CAS PubMed  Google Scholar 

  71. Astrom SU, Okamura SM, Rine J . Yeast cell-type regulation of DNA repair.Nature 1999;397:310.

    Article CAS PubMed  Google Scholar 

  72. Lee SE, Paques F, Sylvan J, Haber JE . Role of yeastSIR genes and mating type in directing DNA double-strand breaks to homologous and non-homologous repair paths.Curr Biol 1999;9:767–770.

    Article CAS PubMed  Google Scholar 

  73. Nickoloff JA, Haber JE . Mating-type control of DNA repair and recombination inSaccharomyces cerevisiae. In: Nickoloff JA, Hoekstra MF, eds. DNA Damage and Repair, Vol 3: Advances from Phage to Humans. Totowa, NJ: Humana Press, 2001:107–124.

  74. Allen C, Kurimasa A, Brennemann MA, Chen DJ, Nickoloff JA . DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination.Proc Natl Acad Sci USA 2002;99:3758–3763.

    Article CAS PubMed PubMed Central  Google Scholar 

  75. Pierce AJ, Hu P, Han MG, Ellis N, Jasin M . Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells.Genes Dev 2001;15:3237–3242.

    Article CAS PubMed PubMed Central  Google Scholar 

  76. Delacote F, Han M, Stamato TD, Jasin M, Lopez BS . Anxrcc4 defect or Wortmannin stimulates homologous recombination specifically induced by double-strand breaks in mammalian cells.Nucleic Acids Res 2002;30:3454–3463.

    Article CAS PubMed PubMed Central  Google Scholar 

  77. Ooi SL, Shoemaker DD, Boeke JD . A DNA microarray-based genetic screen for nonhomologous end-joining mutants inSaccharomyces cerevisiae.Science 2001;294:2552–2556.

    Article CAS PubMed  Google Scholar 

  78. Valencia M, Bentele M, Vaze MB,et al. NEJ1 controls non-homologous end joining inSaccharomyces cerevisiae.Nature 2001;414:666–669.

    Article CAS PubMed  Google Scholar 

  79. Kegel A, Sjostrand JO, Astrom SU . Nej1p, a cell type-specific regulator of nonhomologous end joining in yeast.Curr Biol 2001;11:1611–1617.

    Article CAS PubMed  Google Scholar 

  80. Valencia-Burton M, Oki M, Johnson J,et al. Different mating-type-regulated genes affect the DNA repair defects of Saccharomyces RAD51, RAD52 and RAD55 mutants.Genetics 2006;174:41–55.

    Article CAS PubMed PubMed Central  Google Scholar 

  81. Yamazoe M, Sonoda E, Hochegger H, Takeda S . Reverse genetic studies of the DNA damage response in the chicken B lymphocyte line DT40.DNA Repair (Amst) 2004;3:1175–1185.

    Article CAS  Google Scholar 

  82. Aladjem MI, Itoh N, Utiyama H, Wahl GM . ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage.Curr Biol 1998;8:145–155.

    Article CAS PubMed  Google Scholar 

  83. Mekeel KL, Tang W, Kachnic LA,et al. Inactivation of p53 results in high-rates of homologous recombination.Oncogene 1997;14:1847–1857.

    Article CAS PubMed  Google Scholar 

  84. Willers H, McCarthy EE, Wu B,et al. Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control.Oncogene 2000;19:632–639.

    Article CAS PubMed  Google Scholar 

  85. Romanova LY, Willers H, Blagosklonny MV, Powell SN . The interaction of p53 with replication protein A mediates suppression of homologous recombination.Oncogene 2004;23:9025–9033.

    Article CAS PubMed  Google Scholar 

  86. Akyuz N, Boehden GS, Susse S,et al. DNA substrate dependence of p53-mediated regulation of double-strand break repair.Mol Cell Biol 2002;22:6306–6317.

    Article CAS PubMed PubMed Central  Google Scholar 

  87. Gatz SA, Wiesmuller L . p53 in recombination and repair.Cell Death Differ 2006;13:1003–1016.

    Article CAS PubMed  Google Scholar 

  88. Yoon D, Wang Y, Stapleford K, Wiesmuller L, Chen J . P53 inhibits strand exchange and replication fork regression promoted by human Rad51.J Mol Biol 2004;336:639–654.

    Article CAS PubMed  Google Scholar 

  89. Orii KE, Lee Y, Kondo N, McKinnon PJ . Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development.Proc Natl Acad Sci USA 2006;103:10017–10022.

    Article CAS PubMed PubMed Central  Google Scholar 

  90. Kadyk LC, Hartwell LH . Sister chromatids are preferred over homologs as substrates for recombinational repair inSaccharomyces cerevisiae.Genetics 1992;132:387–402.

    CAS PubMed PubMed Central  Google Scholar 

  91. Watrin E, Peters JM . Cohesin and DNA damage repair.Exp Cell Res 2006;312:2687–2693.

    Article CAS PubMed  Google Scholar 

  92. Takata M, Sasaki MS, Sonoda E,et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells.EMBO J 1998;17:5497–5508.

    Article CAS PubMed PubMed Central  Google Scholar 

  93. Chen FQ, Nastasi A, Shen ZY,et al. Cell cycle-dependent protein expression of mammalian homologs of yeast DNA double-strand break repair genesRAD51 andRAD52.Mutat Res 1997;384:205–211.

    Article CAS PubMed  Google Scholar 

  94. Toone WM, Aerne BL, Morgan BA, Johnston LH . Getting started: regulating the initiation of DNA replication in yeast.Annu Rev Microbiol 1997;51:125–149.

    Article CAS PubMed  Google Scholar 

  95. Ira G, Pellicioli A, Balijja A,et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1.Nature 2004;431:1011–1017.

    Article CAS PubMed PubMed Central  Google Scholar 

  96. Aylon Y, Liefshitz B, Kupiec M . The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle.EMBO J 2004;23:4868–4875.

    Article CAS PubMed PubMed Central  Google Scholar 

  97. Ferreira MG, Cooper JP . The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions.Mol Cell 2001;7:55–63.

    Article CAS PubMed  Google Scholar 

  98. Caspari T, Murray JM, Carr AM . Cdc2-cyclin B kinase activity links Crb2 and Rqh1-topoisomerase III.Genes Dev 2002;16:1195–1208.

    Article CAS PubMed PubMed Central  Google Scholar 

  99. Esashi F, Christ N, Gannon J,et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.Nature 2005;434:598–604.

    Article CAS PubMed  Google Scholar 

  100. Esashi F, Galkin VE, Yu X, Egelman EH, West SC . Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2.Nat Struct Mol Biol 2007;14:468–474.

    Article CAS PubMed  Google Scholar 

  101. Douglas P, Sapkota GP, Morrice N,et al. Identification ofin vitro andin vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase.Biochem J 2002;368:243–251.

    Article CAS PubMed PubMed Central  Google Scholar 

  102. Chan DW, Chen BP-C, Prithivirasingh S,et al. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks.Genes Dev 2002;16:2333–2338.

    Article CAS PubMed PubMed Central  Google Scholar 

  103. Chen BP, Chan DW, Kobayashi J,et al. Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks.J Biol Chem 2005;280:14709–14715.

    Article CAS PubMed  Google Scholar 

  104. Douglas P, Cui X, Block WD,et al. The DNA-dependent protein kinase catalytic subunit is phosphorylatedin vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain.Mol Cell Biol 2007;27:1581–1591.

    Article CAS PubMed  Google Scholar 

  105. Kurimasa A, Kumano S, Boubnov NV,et al. Requirement for the kinase activity of human DNA-dependent protein kinase catalytic subunit in DNA strand break rejoining.Mol Cell Biol 1999;19:3877–3884.

    Article CAS PubMed PubMed Central  Google Scholar 

  106. Ding Q, Reddy YV, Wang W,et al. Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair.Mol Cell Biol 2003;23:5836–5848.

    Article CAS PubMed PubMed Central  Google Scholar 

  107. Lee SE, Mitchell RA, Cheng A, Hendrickson EA . Evidence for DNA-PK-dependent and DNA-PK-independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle.Mol Cell Biol 1997;17:1425–1433.

    Article CAS PubMed PubMed Central  Google Scholar 

  108. Roth D, Wilson JH . Relative rates of homologous and nonhomologous recombination in transfected DNA.Proc Natl Acad Sci USA 1985;82:3355–3359.

    Article CAS PubMed PubMed Central  Google Scholar 

  109. Haber JE . Partners and pathways: repairing a double-strand break.Trends Biochem Sci 2000;16:259–264.

    CAS  Google Scholar 

  110. Baumann P, West SC . Role of the human RAD51 protein in homologous recombination and double-stranded break repair.Trends Biochem Sci 1998;23:247–251.

    Article CAS PubMed  Google Scholar 

  111. Haber JE . The many interfaces of Mre11.Cell 1998;95:583–586.

    Article CAS PubMed  Google Scholar 

  112. Kim JS, Krasieva TB, Kurumizaka H,et al. Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells.J Cell Biol 2005;170:341–347.

    Article CAS PubMed PubMed Central  Google Scholar 

  113. Chen JJ, Silver D, Cantor S, Livingston DM, Scully R . BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway.Cancer Res 1999;59:S1752–S1756.

    Google Scholar 

  114. Chen J, Silver DP, Walpita D,et al. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.Mol Cell 1998;2:317–328.

    Article CAS PubMed  Google Scholar 

  115. Gudmundsdottir K, Ashworth A . The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability.Oncogene 2006;25:5864–5874.

    Article CAS PubMed  Google Scholar 

  116. Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M . Direct DNA binding by Brca1.Proc Natl Acad Sci USA 2001;98:6086–6091.

    Article CAS PubMed PubMed Central  Google Scholar 

  117. Zhuang J, Zhang J, Willers H,et al. Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining.Cancer Res 2006;66:1401–1408.

    Article CAS PubMed  Google Scholar 

  118. Downey M, Durocher D . γH2AX as a checkpoint maintenance signal.Cell Cycle 2006;5:1376–1381.

    Article CAS PubMed  Google Scholar 

  119. Downs JA, Lowndes NF, Jackson SP . A role forSaccharomyces cerevisiae histone H2A in DNA repair.Nature 2000;408:1001–1004.

    Article CAS PubMed  Google Scholar 

  120. Moore JD, Yazgan O, Ataian Y, Krebs JE . Diverse roles for histone H2A modifications in DNA damage response pathways in yeast.Genetics 2007;176:15–25.

    Article CAS PubMed PubMed Central  Google Scholar 

  121. Xie A, Puget N, Shim I,et al. Control of sister chromatid recombination by histone H2AX.Mol Cell 2004;16:1017–1025.

    Article CAS PubMed  Google Scholar 

  122. Wu S, Shi Y, Mulligan P,et al. A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair.Nat Struct Mol Biol 2007 Nov 18; doi:10.1038/nsmb1332.

    Article CAS  Google Scholar 

  123. Osley MA, Tsukuda T, Nickoloff JA . ATP-dependent chromatin remodeling factors and DNA damage repair.Mutat Res 2007;618:65–80.

    Article CAS PubMed PubMed Central  Google Scholar 

  124. Downs JA, Nussenzweig MC, Nussenzweig A . Chromatin dynamics and the preservation of genetic information.Nature 2007;447:951–958.

    Article CAS PubMed  Google Scholar 

  125. Saberi A, Hochegger H, Szuts D,et al. RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair.Mol Cell Biol 2007;27:2562–2571.

    Article CAS PubMed PubMed Central  Google Scholar 

  126. Dominguez-Bendala J, Masutani M, McWhir J . Down-regulation of PARP-1, but not of Ku80 or DNA-PKcs', results in higher gene targeting efficiency.Cell Biol Int 2006;30:389–393.

    Article CAS PubMed  Google Scholar 

  127. Allen C, Halbrook J, Nickoloff JA . Interactive competition between homologous recombination and non-homologous end joining.Mol Cancer Res 2003;1:913–920.

    CAS PubMed  Google Scholar 

  128. Chan DW, Lees-Miller SP . The DNA-dependent protein kinase is inactivated by autophosphorylation of the catalytic subunit.J Biol Chem 1996;271:8936–8941.

    Article CAS PubMed  Google Scholar 

  129. Calsou P, Frit P, Humbert O,et al. The DNA-dependent protein kinase catalytic activity regulates DNA end processing by means of Ku entry into DNA.J Biol Chem 1999;274:7848–7856.

    Article CAS PubMed  Google Scholar 

  130. Merkle D, Douglas P, Moorhead GBG,et al. The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation.Biochemistry 2002;41:12706–12714.

    Article CAS PubMed  Google Scholar 

  131. Douglas P, Moorhead GBG, Ye RQ, Lees-Miller SP . Protein phosphatases regulate DNA-dependent protein kinase activity.J Biol Chem 2001;276:18992–18998.

    Article CAS PubMed  Google Scholar 

  132. Block WD, Yu Y, Merkle D,et al. Autophosphorylation-dependent remodeling of the DNA-dependent protein kinase catalytic subunit regulates ligation of DNA ends.Nucleic Acids Res 2004;32:4351–4357.

    Article CAS PubMed PubMed Central  Google Scholar 

  133. Reddy YV, Ding Q, Lees-Miller SP, Meek K, Ramsden DA . Non-homologous end joining requires that the DNA-PK complex undergo an autophosphorylation-dependent rearrangement at DNA ends.J Biol Chem 2004;279:39408–39413.

    Article CAS PubMed  Google Scholar 

  134. Convery E, Shin EK, Ding Q,et al. Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs).Proc Natl Acad Sci USA 2005;102:1345–1350.

    Article CAS PubMed PubMed Central  Google Scholar 

  135. Peng Y, Woods RG, Beamish H,et al. Deficiency in the catalytic subunit of DNA-dependent protein kinase causes down-regulation of ATM.Cancer Res 2005;65:1670–1677.

    Article CAS PubMed  Google Scholar 

  136. Chen BP, Uematsu N, Kobayashi J,et al. Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break.J Biol Chem 2007;282:6582–6587.

    Article CAS PubMed  Google Scholar 

  137. Meyn MS . High spontaneous intrachromosomal recombination rates in ataxia-telangiectasia.Science 1993;260:1327–1330.

    Article CAS PubMed  Google Scholar 

  138. Morrison C, Sonoda E, Takao N,et al. The controlling role of ATM in homologous recombinational repair of DNA damage.EMBO J 2000;19:463–471.

    Article CAS PubMed PubMed Central  Google Scholar 

  139. Luo C-M, Tang W, Mekeel KL,et al. High frequency and error-prone DNA recombination in ataxia telangiectasia cell lines.J Biol Chem 1996;271:4497–4503.

    Article CAS PubMed  Google Scholar 

  140. Bolderson E, Scorah J, Helleday T, Smythe C, Meuth M . ATM is required for the cellular response to thymidine induced replication fork stress.Hum Mol Genet 2004;13:2937–2945.

    Article CAS PubMed  Google Scholar 

  141. Sakamoto S, Iijima K, Mochizuki D,et al. Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions.Oncogene 2007;26:6002–6009.

    Article CAS PubMed  Google Scholar 

  142. Barchi M, Mahadevaiah S, Di Giacomo M,et al. Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage.Mol Cell Biol 2005;25:7203–7215.

    Article CAS PubMed PubMed Central  Google Scholar 

  143. Wang H, Boecker W, Wang H,et al. Caffeine inhibits homology directed repair of I-SceI induced DNA double-strand breaks.Oncogene 2004;23:824–834.

    Article CAS PubMed  Google Scholar 

  144. Hickson I, Zhao Y, Richardson CJ,et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM.Cancer Res 2004;64:9152–9159.

    Article CAS PubMed  Google Scholar 

  145. Lundin C, Erixon K, Arnaudeau C,et al. Different roles for nonhomologous end joining and homologous recombination following replication arrest in mammalian cells.Mol Cell Biol 2002;22:5869–5878.

    Article CAS PubMed PubMed Central  Google Scholar 

  146. Kuhne M, Riballo E, Rief N,et al. A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity.Cancer Res 2004;64:500–508.

    Article PubMed  Google Scholar 

  147. Bredemeyer AL, Sharma GG, Huang CY,et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination.Nature 2006;442:466–470.

    Article CAS PubMed  Google Scholar 

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Acknowledgements

We thank D Chen and BPC Chen (University of Texas Southwestern Medical Center, USA), S Lees-Miller (University of Calgary, Canada), K Meek (Michigan State University, USA), MA Osley (University of New Mexico, USA), and members of the Nickoloff lab for helpful discussions and excellent collaborations. Our research on the NHEJ/HR interface is supported by National Cancer Institute Grant R01 CA100862 to JA Nickoloff.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine and Cancer Center, Albuquerque, 87131, NM, USA

    Meena Shrivastav, Leyma P De Haro & Jac A Nickoloff

Authors
  1. Meena Shrivastav
  2. Leyma P De Haro
  3. Jac A Nickoloff

Corresponding author

Correspondence toJac A Nickoloff.

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