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Regulation of DNA repair throughout the cell cycle

Key Points

  • The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for maintaining genome integrity.

  • The types of DNA lesion and the checkpoint pathways that are activated in response to DNA damage influence the DNA-repair pathways according to the cell-cycle phase.

  • Failure to coordinate DNA repair with cell-cycle progression can cause genome instability, cell death and cancer.

  • Phosphorylation events that are mediated by cyclin-dependent kinases and checkpoints regulate DNA repair according to the cell-cycle stage.

  • Certain DNA-repair pathways are attenuated in non-dividing cells that probably possess dedicated mechanisms to repair endogenous lesions.

  • SUMO and ubiquitin modifications are crucial in the regulation of the stability and activity of key components of DNA repair and checkpoint machineries, thereby regulating important cell-cycle events.

Abstract

The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for genome integrity. DNA lesions activate checkpoint pathways that regulate specific DNA-repair mechanisms in the different phases of the cell cycle. Checkpoint-arrested cells resume cell-cycle progression once damage has been repaired, whereas cells with unrepairable DNA lesions undergo permanent cell-cycle arrest or apoptosis. Recent studies have provided insights into the mechanisms that contribute to DNA repair in specific cell-cycle phases and have highlighted the mechanisms that ensure cell-cycle progression or arrest in normal and cancerous cells.

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Figure 1: Cell-cycle-specific DNA structures and lesions and the checkpoint kinases that respond to them.
Figure 2: cyclin-dependent-kinase- and checkpoint-mediated regulatory processes influence DNA-repair pathways.
Figure 3: Repair of double-strand breaks by non-homologous end joining and homologous recombination.
Figure 4: Sumoylation and ubiquitylation events that are implicated in modulation of DNA repair.

References

  1. 1

    Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).

    CAS  Google Scholar 

  2. 2

    Vermeulen, K., Van Bockstaele, D. R. & Berneman, Z. N. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 36, 131–149 (2003).

    CAS  Google Scholar 

  3. 3

    Aguilera, A. The connection between transcription and genomic instability. EMBO J. 21, 195–201 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Branzei, D. & Foiani, M. The DNA damage response during DNA replication. Curr. Opin. Cell Biol. 17, 568–575 (2005).

    CAS  Google Scholar 

  5. 5

    Strom, L. & Sjogren, C. Chromosome segregation and double-strand break repair — a complex connection. Curr. Opin. Cell Biol. 19, 344–349 (2007).

    Google Scholar 

  6. 6

    Wang, J. C. Cellular roles of DNA topoisomerases: a molecular perspective. Nature Rev. Mol. Cell Biol. 3, 430–440 (2002).

    CAS  Google Scholar 

  7. 7

    Branzei, D. & Foiani, M. The Rad53 signal transduction pathway: replication fork stabilization, DNA repair, and adaptation. Exp. Cell Res. 312, 2654–2659 (2006).

    CAS  Google Scholar 

  8. 8

    Bartek, J. & Lukas, J. DNA damage checkpoints: from initiation to recovery or adaptation. Curr. Opin. Cell Biol. 19, 238–245 (2007).

    CAS  Google Scholar 

  9. 9

    Neecke, H., Lucchini, G. & Longhese, M. P. Cell cycle progression in the presence of irreparable DNA damage is controlled by a Mec1- and Rad53-dependent checkpoint in budding yeast. EMBO J. 18, 4485–4497 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Giannattasio, M., Lazzaro, F., Longhese, M. P., Plevani, P. & Muzi-Falconi, M. Physical and functional interactions between nucleotide excision repair and DNA damage checkpoint. EMBO J. 23, 429–438 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Pellicioli, A., Lee, S. E., Lucca, C., Foiani, M. & Haber, J. E. Regulation of Saccharomyces Rad53 checkpoint kinase during adaptation from DNA damage-induced G2/M arrest. Mol. Cell 7, 293–300 (2001).

    CAS  Google Scholar 

  12. 12

    Ira, G. et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011–1017 (2004). Presents the first evidence that CDK1 activity is required for DSB end resection and so influences the choice of the DSBR pathway according to the cell-cycle phase.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Jazayeri, A. et al. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nature Cell Biol. 8, 37–45 (2006). Shows a dependency of ATR activation on ATM, MRN and CDK activity, and demonstrates the link between ATR activation and HR repair.

    CAS  PubMed  Google Scholar 

  14. 14

    Cotta-Ramusino, C. et al. Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells. Mol. Cell 17, 153–159 (2005).

    CAS  Google Scholar 

  15. 15

    Elledge, S. J. Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664–1672 (1996).

    CAS  PubMed  Google Scholar 

  16. 16

    Falck, J., Coates, J. & Jackson, S. P. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611 (2005).

    CAS  PubMed  Google Scholar 

  17. 17

    You, Z., Chahwan, C., Bailis, J., Hunter, T. & Russell, P. ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol. Cell Biol. 25, 5363–5379 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

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

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007). Identifies a comprehensive catalogue of ATM and ATR targets and provides evidence that they are bona fide members of the DDR network.

    CAS  Google Scholar 

  20. 20

    Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  Google Scholar 

  21. 21

    Karagiannis, T. C. & El-Osta, A. Chromatin modifications and DNA double-strand breaks: the current state of play. Leukemia 21, 195–200 (2007).

    CAS  Google Scholar 

  22. 22

    Groth, A., Rocha, W., Verreault, A. & Almouzni, G. Chromatin challenges during DNA replication and repair. Cell 128, 721–733 (2007).

    CAS  Google Scholar 

  23. 23

    Shibutani, S., Takeshita, M. & Grollman, A. P. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349, 431–434 (1991).

    CAS  Google Scholar 

  24. 24

    Soussi, T. & Beroud, C. Significance of TP53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides. Hum. Mutat. 21, 192–200 (2003).

    CAS  Google Scholar 

  25. 25

    Russo, M. T. et al. Accumulation of the oxidative base lesion 8-hydroxyguanine in DNA of tumor-prone mice defective in both the Myh and Ogg1 DNA glycosylases. Cancer Res. 64, 4411–4414 (2004).

    CAS  Google Scholar 

  26. 26

    Nojima, K. et al. Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res. 65, 11704–11711 (2005).

    CAS  Google Scholar 

  27. 27

    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 5, 1021–1029 (2006).

    CAS  Google Scholar 

  28. 28

    Paques, F. & Haber, J. E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63, 349–404 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Krogh, B. O. & Symington, L. S. Recombination proteins in yeast. Annu. Rev. Genet. 38, 233–271 (2004).

    CAS  Google Scholar 

  30. 30

    Takata, M. 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. 17, 5497–5508 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lee, S. E., Mitchell, R. A., Cheng, A. & Hendrickson, E. A. Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle. Mol. Cell Biol. 17, 1425–1433 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Astrom, S. U., Okamura, S. M. & Rine, J. Yeast cell-type regulation of DNA repair. Nature 397, 310 (1999).

    CAS  Google Scholar 

  33. 33

    Lee, S. E., Paques, F., Sylvan, J. & Haber, J. E. Role of yeast SIR genes and mating type in directing DNA double-strand breaks to homologous and non-homologous repair paths. Curr. Biol. 9, 767–770 (1999).

    CAS  Google Scholar 

  34. 34

    Jiricny, J. The multifaceted mismatch-repair system. Nature Rev. Mol. Cell Biol. 7, 335–346 (2006).

    CAS  Google Scholar 

  35. 35

    Lettier, G. et al. The role of DNA double-strand breaks in spontaneous homologous recombination in S. cerevisiae. PLoS Genet. 2, e194 (2006).

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Fabre, F., Chan, A., Heyer, W. D. & Gangloff, S. Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication. Proc. Natl Acad. Sci. USA 99, 16887–16892 (2002).

    CAS  PubMed  Google Scholar 

  37. 37

    Branzei, D. & Foiani, M. Interplay of replication checkpoints and repair proteins at stalled replication forks. DNA Repair 6, 994–1003 (2007).

    CAS  Google Scholar 

  38. 38

    Lehmann, A. R. et al. Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair 6, 891–899 (2007).

    CAS  Google Scholar 

  39. 39

    Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G. & Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141 (2002). Presents the first evidence that PCNA is modified by ubiquitin and SUMO and demonstrates that PCNA polyubiquitylation is required for PRR.

    CAS  Google Scholar 

  40. 40

    Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nature Rev. Mol. Cell Biol. 7, 739–750 (2006).

    CAS  Google Scholar 

  41. 41

    Nakada, D., Hirano, Y. & Sugimoto, K. Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway. Mol. Cell Biol. 24, 10016–10025 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Llorente, B. & Symington, L. S. The Mre11 nuclease is not required for 5′ to 3′ resection at multiple HO-induced double-strand breaks. Mol. Cell Biol. 24, 9682–9694 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Limbo, O. et al. Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Mol. Cell 28, 134–146 (2007). Together with reference 44, this paper documents the ability of Ctp1 (or CtIP in mammals) to function together with the MRX (or MRN in mammals) complex in DSB resection and promote HR in the S and G2 phases of the cell cycle.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Sartori, A. A. et al. Human CtIP promotes DNA end resection. Nature 450, 509–514 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Aylon, Y. & Kupiec, M. New insights into the mechanism of homologous recombination in yeast. Mutat. Res. 566, 231–248 (2004).

    CAS  Google Scholar 

  46. 46

    Kim, J. S. et al. Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells. J. Cell Biol. 170, 341–347 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Hochegger, H. et al. PARP-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells. EMBO J. 25, 1305–1314 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Saberi, A. 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. 27, 2562–2571 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Barber, L. J. & Boulton, S. J. BRCA1 ubiquitylation of CtIP: just the tIP of the iceberg? DNA Repair 5, 1499–1504 (2006).

    CAS  Google Scholar 

  50. 50

    Yu, X. & Baer, R. Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J. Biol. Chem. 275, 18541–18549 (2000).

    CAS  Google Scholar 

  51. 51

    Hirano, T. At the heart of the chromosome: SMC proteins in action. Nature Rev. Mol. Cell Biol. 7, 311–322 (2006).

    CAS  Google Scholar 

  52. 52

    Uhlmann, F. & Nasmyth, K. Cohesion between sister chromatids must be established during DNA replication. Curr. Biol. 8, 1095–1101 (1998).

    CAS  Google Scholar 

  53. 53

    Skibbens, R. V., Corson, L. B., Koshland, D. & Hieter, P. Ctf7p is essential for sister chromatid cohesion and links mitotic chromosome structure to the DNA replication machinery. Genes Dev. 13, 307–319 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Strom, L. et al. Postreplicative formation of cohesion is required for repair and induced by a single DNA break. Science 317, 242–245 (2007).

    Google Scholar 

  55. 55

    Unal, E., Heidinger-Pauli, J. M. & Koshland, D. DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science 317, 245–248 (2007).

    Google Scholar 

  56. 56

    Sjogren, C. & Nasmyth, K. Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr. Biol. 11, 991–995 (2001).

    CAS  Google Scholar 

  57. 57

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

    Google Scholar 

  58. 58

    Unal, E. et al. DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol. Cell 16, 991–1002 (2004).

    Google Scholar 

  59. 59

    Bermejo, R. et al. Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation. Genes Dev. 21, 1921–1936 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Franchitto, A., Oshima, J. & Pichierri, P. The G2-phase decatenation checkpoint is defective in Werner syndrome cells. Cancer Res. 63, 3289–3295 (2003).

    CAS  Google Scholar 

  61. 61

    Deming, P. B. et al. The human decatenation checkpoint. Proc. Natl Acad. Sci. USA 98, 12044–12049 (2001).

    CAS  Google Scholar 

  62. 62

    Deming, P. B., Flores, K. G., Downes, C. S., Paules, R. S. & Kaufmann, W. K. ATR enforces the topoisomerase II-dependent G2 checkpoint through inhibition of Plk1 kinase. J. Biol. Chem. 277, 36832–36838 (2002).

    CAS  Google Scholar 

  63. 63

    Nouspikel, T. DNA repair in differentiated cells: some new answers to old questions. Neuroscience 145, 1213–1221 (2007).

    CAS  Google Scholar 

  64. 64

    Wilson, D. M. 3rd & McNeill, D. R. Base excision repair and the central nervous system. Neuroscience 145, 1187–1200 (2007).

    CAS  Google Scholar 

  65. 65

    Fishel, M. L., Vasko, M. R. & Kelley, M. R. DNA repair in neurons: so if they don't divide what's to repair? Mutat. Res. 614, 24–36 (2007).

    CAS  Google Scholar 

  66. 66

    Lindahl, T., Karran, P. & Wood, R. D. DNA excision repair pathways. Curr. Opin. Genet. Dev. 7, 158–169 (1997).

    CAS  Google Scholar 

  67. 67

    Lisby, M., Barlow, J. H., Burgess, R. C. & Rothstein, R. Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118, 699–713 (2004).

    CAS  Google Scholar 

  68. 68

    Yuan, S. S., Chang, H. L. & Lee, E. Y. Ionizing radiation-induced Rad51 nuclear focus formation is cell cycle-regulated and defective in both ATM−/− and c-Abl−/− cells. Mutat. Res. 525, 85–92 (2003).

    CAS  Google Scholar 

  69. 69

    Morrison, C. et al. The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J. 19, 463–471 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Caspari, T., Murray, J. M. & Carr, A. M. Cdc2-cyclin B kinase activity links Crb2 and Rqh1-topoisomerase III. Genes Dev. 16, 1195–1208 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Sorensen, C. S. et al. The cell-cycle checkpoint kinase CHK1 is required for mammalian homologous recombination repair. Nature Cell Biol. 7, 195–201 (2005).

    CAS  Google Scholar 

  72. 72

    Sleeth, K. M. et al. RPA mediates recombination repair during replication stress and is displaced from DNA by checkpoint signalling in human cells. J. Mol. Biol. 373, 38–47 (2007).

    CAS  Google Scholar 

  73. 73

    Kai, M., Boddy, M. N., Russell, P. & Wang, T. S. Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress. Genes Dev. 19, 919–932 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Taniguchi, T. et al. Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109, 459–472 (2002).

    CAS  Google Scholar 

  75. 75

    Niedernhofer, L. J. The Fanconi anemia signalosome anchor. Mol. Cell 25, 487–490 (2007).

    CAS  Google Scholar 

  76. 76

    Herzberg, K. et al. Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks. Mol. Cell Biol. 26, 8396–8409 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Flott, S. et al. Phosphorylation of Slx4 by Mec1 and Tel1 regulates the single-strand annealing mode of DNA repair in budding yeast. Mol. Cell Biol. 27, 6433–6445 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Ziv, Y. et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nature Cell Biol. 8, 870–876 (2006).

    CAS  Google Scholar 

  79. 79

    Stucki, M. & Jackson, S. P. γH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. DNA Repair 5, 534–543 (2006).

    CAS  Google Scholar 

  80. 80

    Kim, S. T., Xu, B. & Kastan, M. B. Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev. 16, 560–570 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Yazdi, P. T. et al. SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes Dev. 16, 571–582 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Lopes, M., Foiani, M. & Sogo, J. M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15–27 (2006). Shows physical evidence that TLS and HR mutants accumulate gaps during replication, without affecting fork progression.

    CAS  Google Scholar 

  83. 83

    Kai, M. & Wang, T. S. Checkpoint activation regulates mutagenic translesion synthesis. Genes Dev. 17, 64–76 (2003). Presents evidence that the 911 damage checkpoint interacts physically with DinB, and promotes DinB loading on chromatin and mutagenic bypass of lesions.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Sabbioneda, S. et al. The 9-1-1 checkpoint clamp physically interacts with polzeta and is partially required for spontaneous polzeta-dependent mutagenesis in Saccharomyces cerevisiae. J. Biol. Chem. 280, 38657–38665 (2005).

    CAS  Google Scholar 

  85. 85

    Lehmann, A. R. & Fuchs, R. P. Gaps and forks in DNA replication: rediscovering old models. DNA Repair 5, 1495–1498 (2006).

    CAS  Google Scholar 

  86. 86

    Kai, M., Furuya, K., Paderi, F., Carr, A. M. & Wang, T. S. Rad3-dependent phosphorylation of the checkpoint clamp regulates repair-pathway choice. Nature Cell Biol. 9, 691–697 (2007). Shows that ATM/ATR-dependent phosphorylation of the 911 damage checkpoint promotes Rad6- mediated repair.

    CAS  Google Scholar 

  87. 87

    Liberi, G. et al. Srs2 DNA helicase is involved in checkpoint response and its regulation requires a functional Mec1-dependent pathway and Cdk1 activity. EMBO J. 19, 5027–5038 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Ruffner, H., Jiang, W., Craig, A. G., Hunter, T. & Verma, I. M. BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol. Cell Biol. 19, 4843–4854 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Esashi, F. & Yanagida, M. Cdc2 phosphorylation of Crb2 is required for reestablishing cell cycle progression after the damage checkpoint. Mol. Cell 4, 167–174 (1999).

    CAS  Google Scholar 

  90. 90

    Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. BRCA1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    CAS  Google Scholar 

  91. 91

    Yu, X., Fu, S., Lai, M., Baer, R. & Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20, 1721–1726 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Zhao, G. Y. et al. A critical role for the ubiquitin-conjugating enzyme UBC13 in initiating homologous recombination. Mol. Cell 25, 663–675 (2007). Provides the first evidence that the ubiquitin-conjugating activity of UBC13 is required for DSB repair.

    CAS  Google Scholar 

  93. 93

    Ira, G., Malkova, A., Liberi, G., Foiani, M. & Haber, J. E. Srs2 and Sgs1–Top3 suppress crossovers during double-strand break repair in yeast. Cell 115, 401–411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Robert, T., Dervins, D., Fabre, F. & Gangloff, S. Mrc1 and Srs2 are major actors in the regulation of spontaneous crossover. EMBO J. 25, 2837–2846 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Branzei, D. & Foiani, M. RecQ helicases queuing with Srs2 to disrupt Rad51 filaments and suppress recombination. Genes Dev. 21, 3019–3026 (2007).

    CAS  Google Scholar 

  96. 96

    Esashi, F. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598–604 (2005). Identifies CDK-dependent phosphorylation of BRCA2 and provides evidence that this modification might function as a molecular switch to regulate RAD51 recombination activity.

    CAS  Google Scholar 

  97. 97

    Yang, H., Li, Q., Fan, J., Holloman, W. K. & Pavletich, N. P. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction. Nature 433, 653–657 (2005).

    CAS  Google Scholar 

  98. 98

    Huen, M. S. et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131, 901–914 (2007). References 98, 99, 100 and 102 show that the ubiquitin-ligase activity of RNF8 integrates phosphorylation and ubiquitin signalling that is required for DNA repair and checkpoint response.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Kolas, N. K. et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318, 1637–1640 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007).

    CAS  Google Scholar 

  101. 101

    Plans, V., Guerra-Rebollo, M. & Thomson, T. M. Regulation of mitotic exit by the RNF8 ubiquitin ligase. Oncogene 3 September 2007 (doi:10.1038/sj.onc.1210782).

    Google Scholar 

  102. 102

    Wang, B. & Elledge, S. J. 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 (2007).

    CAS  Google Scholar 

  103. 103

    Gutierrez, G. J. & Ronai, Z. Ubiquitin and SUMO systems in the regulation of mitotic checkpoints. Trends Biochem. Sci. 31, 324–332 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Watanabe, N. et al. Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Proc. Natl Acad. Sci. USA 102, 11663–11668 (2005).

    CAS  Google Scholar 

  105. 105

    Busino, L., Chiesa, M., Draetta, G. F. & Donzelli, M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 23, 2050–2056 (2004).

    CAS  Google Scholar 

  106. 106

    Busino, L. et al. Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage. Nature 426, 87–91 (2003).

    CAS  Google Scholar 

  107. 107

    Jin, J. et al. SCF-βTRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 17, 3062–3074 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Chen, M. S., Ryan, C. E. & Piwnica-Worms, H. Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding. Mol. Cell Biol. 23, 7488–7497 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Smogorzewska, A. et al. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129, 289–301 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Machida, Y. J. et al. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol. Cell 23, 589–596 (2006).

    CAS  Google Scholar 

  111. 111

    Meetei, A. R., Yan, Z. & Wang, W. FANCL replaces BRCA1 as the likely ubiquitin ligase responsible for FANCD2 monoubiquitination. Cell Cycle 3, 179–181 (2004).

    CAS  Google Scholar 

  112. 112

    Andreassen, P. R., D'Andrea, A. D. & Taniguchi, T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 18, 1958–1963 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Ruffner, H., Joazeiro, C. A., Hemmati, D., Hunter, T. & Verma, I. M. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc. Natl Acad. Sci. USA 98, 5134–5139 (2001).

    CAS  Google Scholar 

  114. 114

    Hashizume, R. et al. The RING heterodimer BRCA1–BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 276, 14537–14540 (2001).

    CAS  Google Scholar 

  115. 115

    Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).

    CAS  Google Scholar 

  116. 116

    Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Sobhian, B. et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Stelter, P. & Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188–191 (2003). Together with reference 119, this paper provides the first evidence that PCNA monoubiquitylation promotes the TLS damage-tolerance pathway.

    CAS  Google Scholar 

  119. 119

    Kannouche, P. L., Wing, J. & Lehmann, A. R. Interaction of human DNA polymerase ɛ with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol. Cell 14, 491–500 (2004).

    CAS  Google Scholar 

  120. 120

    Watanabe, K. et al. Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J. 23, 3886–3896 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Plosky, B. S. et al. Controlling the subcellular localization of DNA polymerases ι and ɛ via interactions with ubiquitin. EMBO J. 25, 2847–2855 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Pfander, B., Moldovan, G. L., Sacher, M., Hoege, C. & Jentsch, S. SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436, 428–433 (2005).

    CAS  Google Scholar 

  123. 123

    Papouli, E. et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol. Cell 19, 123–133 (2005). References 122 and 123 show that sumoylated PCNA interacts with Srs2 to regulate recombination.

    CAS  Google Scholar 

  124. 124

    Sacher, M., Pfander, B., Hoege, C. & Jentsch, S. Control of Rad52 recombination activity by double-strand break-induced SUMO modification. Nature Cell Biol. 8, 1284–1290 (2006).

    CAS  Google Scholar 

  125. 125

    Dieckhoff, P., Bolte, M., Sancak, Y., Braus, G. H. & Irniger, S. Smt3/SUMO and Ubc9 are required for efficient APC/C-mediated proteolysis in budding yeast. Mol. Microbiol. 51, 1375–1387 (2004).

    CAS  Google Scholar 

  126. 126

    Zhao, X. & Blobel, G. A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization. Proc. Natl Acad. Sci. USA 102, 4777–4782 (2005).

    CAS  Google Scholar 

  127. 127

    Torres-Rosell, J. et al. The Smc5–Smc6 complex and SUMO modification of Rad52 regulates recombinational repair at the ribosomal gene locus. Nature Cell Biol. 9, 923–931 (2007).

    CAS  Google Scholar 

  128. 128

    Veaute, X. et al. The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments. Nature 423, 309–312 (2003).

    CAS  Google Scholar 

  129. 129

    Krejci, L. et al. DNA helicase Srs2 disrupts the Rad51 presynaptic filament. Nature 423, 305–309 (2003).

    CAS  Google Scholar 

  130. 130

    Bugreev, D. V., Yu, X., Egelman, E. H. & Mazin, A. V. Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. Genes Dev. 21, 3085–3094 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Hu, Y. et al. RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. Genes Dev. 21, 3073–3084 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Liberi, G. et al. Rad51-dependent DNA structures accumulate at damaged replication forks in sgs1 mutants defective in the yeast ortholog of BLM RecQ helicase. Genes Dev. 19, 339–350 (2005). This study and reference 134 provide different types of evidence that the helicase Sgs1 (or BLM in mammals) cooperates with topoisomerase III to dissolve dHJ and pseudo-dHJ, and thus to modulate the outcome of recombination events.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Mankouri, H. W. & Hickson, I. D. Top3 processes recombination intermediates and modulates checkpoint activity after DNA damage. Mol. Biol. Cell 17, 4473–4483 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Wu, L. & Hickson, I. D. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870–874 (2003).

    CAS  Google Scholar 

  135. 135

    Branzei, D. et al. Ubc9- and Mms21-mediated sumoylation counteracts recombinogenic events at damaged replication forks. Cell 127, 509–522 (2006). Provides physical evidence that Ubc9- and Mms21-dependent sumoylation functions to prevent recombinogenic structures from accumulating during replication of damaged templates.

    CAS  PubMed  Google Scholar 

  136. 136

    Eladad, S. et al. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Hum. Mol. Genet. 14, 1351–1365 (2005).

    CAS  Google Scholar 

  137. 137

    De Piccoli, G. et al. Smc5–Smc6 mediate DNA double-strand-break repair by promoting sister-chromatid recombination. Nature Cell Biol. 8, 1032–1034 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Torres-Rosell, J. et al. SMC5 and SMC6 genes are required for the segregation of repetitive chromosome regions. Nature Cell Biol. 7, 412–419 (2005).

    CAS  Google Scholar 

  139. 139

    Andrews, E. A. et al. Nse2, a component of the Smc5–6 complex, is a SUMO ligase required for the response to DNA damage. Mol. Cell Biol. 25, 185–196 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Potts, P. R. & Yu, H. Human MMS21/NSE2 is a SUMO ligase required for DNA repair. Mol. Cell Biol. 25, 7021–7032 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    CAS  Google Scholar 

  142. 142

    Kumagai, A. & Dunphy, W. G. Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol. Cell 6, 839–849 (2000).

    CAS  Google Scholar 

  143. 143

    Mamely, I. et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr. Biol. 16, 1950–1955 (2006).

    CAS  Google Scholar 

  144. 144

    Watanabe, N. et al. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCF-βTrCP. Proc. Natl Acad. Sci. USA 101, 4419–4424 (2004).

    CAS  Google Scholar 

  145. 145

    Mailand, N., Bekker-Jensen, S., Bartek, J. & Lukas, J. Destruction of Claspin by SCFβTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol. Cell 23, 307–318 (2006).

    CAS  Google Scholar 

  146. 146

    Peschiaroli, A. et al. SCFβTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol. Cell 23, 319–329 (2006).

    CAS  Google Scholar 

  147. 147

    Geiss-Friedlander, R. & Melchior, F. Concepts in sumoylation: a decade on. Nature Rev. Mol. Cell Biol. 8, 947–956 (2007).

    CAS  Google Scholar 

  148. 148

    Heun, P. SUMOrganization of the nucleus. Curr. Opin. Cell Biol. 19, 350–355 (2007).

    CAS  Google Scholar 

  149. 149

    Seeler, J. S., Bischof, O., Nacerddine, K. & Dejean, A. SUMO, the three Rs and cancer. Curr. Top. Microbiol. Immunol. 313, 49–71 (2007).

    CAS  Google Scholar 

  150. 150

    Burgess, R. C., Rahman, S., Lisby, M., Rothstein, R. & Zhao, X. The Slx5–Slx8 complex affects sumoylation of DNA repair proteins and negatively regulates recombination. Mol. Cell Biol. 27, 6153–6162 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Xie, Y. et al. The yeast Hex3–Slx8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. J. Biol. Chem. 282, 34176–34184 (2007).

    CAS  Google Scholar 

  152. 152

    Prudden, J. et al. SUMO-targeted ubiquitin ligases in genome stability. EMBO J. 26, 4089–4101 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Ulrich, H. D. Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol. 15, 525–532 (2005).

    CAS  Google Scholar 

  154. 154

    Bylebyl, G. R., Belichenko, I. & Johnson, E. S. The SUMO isopeptidase Ulp2 prevents accumulation of SUMO chains in yeast. J. Biol. Chem. 278, 44113–44120 (2003).

    CAS  Google Scholar 

  155. 155

    Lopes, M. et al. The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412, 557–561 (2001).

    CAS  PubMed  Google Scholar 

  156. 156

    Sogo, J. M., Lopes, M. & Foiani, M. Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297, 599–602 (2002).

    CAS  PubMed  Google Scholar 

  157. 157

    Potts, P. R., Porteus, M. H. & Yu, H. Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks. EMBO J. 25, 3377–3388 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Moldovan, G. L., Pfander, B. & Jentsch, S. PCNA controls establishment of sister chromatid cohesion during S phase. Mol. Cell 23, 723–732 (2006).

    CAS  Google Scholar 

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Acknowledgements

The authors apologize for the many interesting articles that could not be cited here owing to space limitations. The work in the authors' laboratories is supported by grants form the Associazione Italiana per la Ricerca sul Cancro, the European Community, Telethon-Italy, the Italian Ministry of Education and the Association for International Cancer Research to M.F. and D.B. D.B. is supported by the Buzzati-Traverso foundation.

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Glossary

Replication fork

The branch-point structure that forms during DNA replication between the two template DNA strands where nascent DNA synthesis is ongoing.

Cyclin-dependent kinases

A group of serine/threonine protein kinases that are activated at specific points during the cell cycle, together with their regulatory cyclin subunits. They regulate cell-cycle transitions by inducing degradation of cell-cycle inhibitory proteins.

Apoptosis

A form of programmed cell death that is well defined in multicellular organisms.

Stalled fork

A replication fork at which progress is blocked. Progress may be blocked by the presence of bulky lesions, aberrant DNA structures, protein–DNA complexes or depletion of dNTP pools.

Collapsed forks

Disjunction of the two partially replicated sister duplexes at the replication fork that is usually associated with the dissociation of the replisome from the replication fork.

Replisome

Protein machinery that is required to replicate DNA.

Translesion-synthesis polymerases

Low-fidelity and non-processive polymerases that can be used to bypass DNA lesions at the replication fork, often in an error-prone way.

Template switch

(TS). A process that repairs gaps in newly replicated DNA. TS can occur, for example, when a replicative polymerase encounters a lesion on the parental strand. TS uses the information on the newly synthesized sister chromatid as a template to fill in the gaps.

Topoisomerases

Enzymes that remove torsional stress from double-stranded DNA by breaking and rejoining one or two of the DNA strands.

Supercoils

Contortions in DNA that are important for DNA packaging and DNA–RNA synthesis. Topoisomerases sense supercoiling and can either generate or dissipate it by changing DNA topology.

Precatenanes

Cruciform junctions that are formed by the intertwining of the sister duplexes in the replicated portion of a replicone.

Damage tolerance

A post-replicative repair pathway in which the lesions are not repaired, but bypassed (tolerated) during replication. Bypass can be achieved by either using specialized polymerases, or by using the newly synthesized sister chromatid strand as a template.

Epistasis

A group of genes that function in the same biological pathway, usually defined by genetic analysis of double mutants.

Poly(ADP-ribose) polymerase

A polymerase that attaches ADP–ribose moieties to target proteins by means of covalent bonds, which is one of the earliest cellular responses to strand breaks.

Differentiated cells

Cells that are specialized for a particular function (such as neurons and muscle cells) and that cannot proliferate.

Senescent cells

Mitotic cells that cannot divide, but remain metabolically active. Senescence is often caused by stimuli that can cause cancer.

Double Holliday junction

A central intermediate to homologous recombination.

Ischaemia

A restriction in blood supply, generally due to factors in the blood vessels, that causes tissue damage or dysfunction.

RecQ helicase

A family of helicase enzymes that is important for genome maintenance. They function through unwinding paired DNA and translocate in the 3′→5′ direction.

Fanconi anaemia

A rare genetically inherited disorder that is characterized by congenital abnormalities and increased incidence of cancer.

Srs2

A budding yeast DNA helicase that functions to prevent recombination by disrupting Rad51 filaments.

BRCA1

The product of the first breast cancer susceptibility gene; it is involved in DNA repair, cell-cycle regulation and protein ubiquitylation.

BRCA2

A tumour suppressor and an integral component of the homologous-recombination machinery.

BRCT repeats

A protein motif with homology to the C-terminal region of BRCA1 that constitutes a phosphopeptide-recognition domain.

Hemicatenanes

Cruciform junctions of two double-stranded DNA molecules in which one of the strands of one duplex passes between the two strands of the other duplex (and vice versa).

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Branzei, D., Foiani, M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9, 297–308 (2008). https://doi.org/10.1038/nrm2351

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