Cell Biochemistry and Biophysics

, Volume 53, Issue 1, pp 17–31 | Cite as

Mechanisms of Dealing with DNA Damage-Induced Replication Problems

  • Magda Budzowska
  • Roland Kanaar
Review Paper


During every S phase, cells need to duplicate their genomes so that both daughter cells inherit complete copies of genetic information. Given the large size of mammalian genomes and the required precision of DNA replication, genome duplication requires highly fine-tuned corrective and quality control processes. A major threat to the accuracy and efficiency of DNA synthesis is the presence of DNA lesions, caused by both endogenous and exogenous damaging agents. Replicative DNA polymerases, which carry out the bulk of DNA synthesis, evolved to do their job extremely precisely and efficiently. However, they are unable to use damaged DNA as a template and, consequently, are stopped at most DNA lesions. Failure to restart such stalled replication forks can result in major chromosomal aberrations and lead to cell dysfunction or death. Therefore, a well-coordinated response to replication perturbation is essential for cell survival and fitness. Here we review how this response involves activating checkpoint signaling and the use of specialized pathways promoting replication restart. Checkpoint signaling adjusts cell cycle progression to the emergency situation and thus gives cells more time to deal with the damage. Replication restart is mediated by two pathways. Homologous recombination uses homologous DNA sequence to repair or bypass the lesion and is therefore mainly error free. Error-prone translesion synthesis employs specialized, low fidelity polymerases to bypass the damage.


DNA damage DNA replication restart Homologous recombination Translesion DNA synthesis 



Work in RK’s laboratory is supported by grants from the Dutch Cancer Society (KWF), the Netherlands Organization for Scientific Research (NWO), the Netherlands Genomics Initiative/NWO, the Association for International Cancer Research (AICR) and the European Commission (Integrated Project 512113).


  1. 1.
    Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for preventing cancer. Nature, 411, 366–374.PubMedGoogle Scholar
  2. 2.
    Zhou, B. B., & Elledge, S. J. (2000). The DNA damage response: Putting checkpoints in perspective. Nature, 408, 433–439.PubMedGoogle Scholar
  3. 3.
    Bartek, J., & Lukas, J. (2001). Pathways governing G1/S transition and their response to DNA damage. FEBS Letters, 490, 117–122.PubMedGoogle Scholar
  4. 4.
    Schuler, M., & Green, D. R. (2001). Mechanisms of p53-dependent apoptosis. Biochemical Society Transactions, 29, 684–688.PubMedGoogle Scholar
  5. 5.
    Branzei, D., & Foiani, M. (2007). Molecular genetics of recombination. In A. Aguilera & R. Rothstein (Eds.), Topics curr genet (pp. 201–219). Germany: Springer Verlag.Google Scholar
  6. 6.
    Niedernhofer, L. J., Odijk, H., Budzowska, M., van Drunen, E., Maas, A., Theil, A. F., et al. (2004). The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Molecular and Cellular Biology, 24, 5776–5787.PubMedGoogle Scholar
  7. 7.
    Hanada, K., Budzowska, M., Davies, S. L., van Drunen, E., Onizawa, H., Beverloo, H. B., et al. (2007). The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nature Structural & Molecular Biology, 14, 1096–1104.Google Scholar
  8. 8.
    Abraham, R. T. (2001). Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes and Development, 15, 2177–2196.PubMedGoogle Scholar
  9. 9.
    Liu, Q., Guntuku, S., Cui, X. S., Matsuoka, S., Cortez, D., Tamai, K., et al. (2000). Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes and Development, 14, 1448–1459.PubMedGoogle Scholar
  10. 10.
    Brown, E. J., & Baltimore, D. (2000). ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes and Development, 14, 397–402.PubMedGoogle Scholar
  11. 11.
    Budzowska, M., Jaspers, I., Essers, J., de Waard, H., van Drunen, E., Hanada, K., et al. (2004). Mutation of the mouse Rad17 gene leads to embryonic lethality and reveals a role in DNA damage-dependent recombination. EMBO Journal, 23, 3548–3558.PubMedGoogle Scholar
  12. 12.
    de Klein, A., Muijtjens, M., van Os, R., Verhoeven, Y., Smit, B., Carr, A. M., et al. (2000). Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Current Biology, 10, 479–482.PubMedGoogle Scholar
  13. 13.
    Zou, L., & Elledge, S. J. (2003). Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science, 300, 1542–1548.PubMedGoogle Scholar
  14. 14.
    St Onge, R. P., Udell, C. M., Casselman, R., & Davey, S. (1999). The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. Molecular Biology of the Cell, 10, 1985–1995.PubMedGoogle Scholar
  15. 15.
    Burtelow, M. A., Roos-Mattjus, P. M., Rauen, M., Babendure, J. R., & Karnitz, L. M. (2001). Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9-1-1) DNA damage responsive checkpoint complex. Journal of Biological Chemistry, 276, 25903–25909.PubMedGoogle Scholar
  16. 16.
    Singh, V. K., Nurmohamed, S., Davey, S. K., & Jia, Z. (2007). Tri-cistronic cloning, overexpression and purification of human Rad9, Rad1, Hus1 protein complex. Protein Expression and Purification, 54, 204–211.PubMedGoogle Scholar
  17. 17.
    Venclovas, C., & Thelen, M. P. (2000). Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes. Nucleic Acids Research, 28, 2481–2493.PubMedGoogle Scholar
  18. 18.
    Kondo, T., Matsumoto, K., & Sugimoto, K. (1999). Role of a complex containing Rad17, Mec3, and Ddc1 in the yeast DNA damage checkpoint pathway. Molecular and Cellular Biology, 19, 1136–1143.PubMedGoogle Scholar
  19. 19.
    Zou, L., Cortez, D., & Elledge, S. J. (2002). Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes and Development, 16, 198–208.PubMedGoogle Scholar
  20. 20.
    Kondo, T., Wakayama, T., Naiki, T., Matsumoto, K., & Sugimoto, K. (2001). Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science, 294, 867–870.PubMedGoogle Scholar
  21. 21.
    Majka, J., & Burgers, P. M. (2004). The PCNA-RFC families of DNA clamps and clamp loaders. Progress in Nucleic Acid Research and Molecular Biology, 78, 227–260.PubMedGoogle Scholar
  22. 22.
    Bermudez, V. P., Lindsey-Boltz, L. A., Cesare, A. J., Maniwa, Y., Griffith, J. D., Hurwitz, J., et al. (2003). Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro. Proceedings of the National Academy of Sciences of the United States of America, 100, 1633–1638.PubMedGoogle Scholar
  23. 23.
    Kumagai, A., Lee, J., Yoo, H. Y., & Dunphy, W. G. (2006). TopBP1 activates the ATR-ATRIP complex. Cell, 124, 943–955.PubMedGoogle Scholar
  24. 24.
    Zhao, H., & Piwnica-Worms, H. (2001). ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Molecular and Cellular Biology, 21, 4129–4139.PubMedGoogle Scholar
  25. 25.
    Capasso, H., Palermo, C., Wan, S., Rao, H., John, U. P., O’Connell, M. J., et al. (2002). Phosphorylation activates Chk1 and is required for checkpoint-mediated cell cycle arrest. Journal of Cell Science, 115, 4555–4564.PubMedGoogle Scholar
  26. 26.
    Chen, P., Luo, C., Deng, Y., Ryan, K., Register, J., Margosiak, S., et al. (2000). The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: Implications for Chk1 regulation. Cell, 100, 681–692.PubMedGoogle Scholar
  27. 27.
    Oe, T., Nakajo, N., Katsuragi, Y., Okazaki, K., & Sagata, N. (2001). Cytoplasmic occurrence of the Chk1/Cdc25 pathway and regulation of Chk1 in Xenopus oocytes. Developmental Biology, 229, 250–261.PubMedGoogle Scholar
  28. 28.
    Smits, V. A., Reaper, P. M., & Jackson, S. P. (2006). Rapid PIKK-dependent release of Chk1 from chromatin promotes the DNA-damage checkpoint response. Current Biology, 16, 150–159.PubMedGoogle Scholar
  29. 29.
    Dronkert, M. L., & Kanaar, R. (2001). Repair of DNA interstrand cross-links. Mutation Research, 486, 217–247.PubMedGoogle Scholar
  30. 30.
    Cox, M. M., Goodman, M. F., Kreuzer, K. N., Sherratt, D. J., Sandler, S. J., & Marians, K. J. (2000). The importance of repairing stalled replication forks. Nature, 404, 37–41.PubMedGoogle Scholar
  31. 31.
    Kostriken, R., Strathern, J. N., Klar, A. J., Hicks, J. B., & Heffron, F. (1983). A site-specific endonuclease essential for mating-type switching in Saccharomyces cerevisiae. Cell, 35, 167–174.PubMedGoogle Scholar
  32. 32.
    Keeney, S., & Neale, M. J. (2006). Initiation of meiotic recombination by formation of DNA double-strand breaks: Mechanism and regulation. Biochemical Society Transactions, 34, 523–525.PubMedGoogle Scholar
  33. 33.
    Deans, B., Griffin, C. S., Maconochie, M., & Thacker, J. (2000). Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO Journal, 19, 6675–6685.PubMedGoogle Scholar
  34. 34.
    Smiraldo, P. G., Gruver, A. M., Osborn, J. C., & Pittman, D. L. (2005). Extensive chromosomal instability in Rad51d-deficient mouse cells. Cancer Research, 65, 2089–2096.PubMedGoogle Scholar
  35. 35.
    Lim, D. S., & Hasty, P. (1996). A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Molecular and Cellular Biology, 16, 7133–7143.PubMedGoogle Scholar
  36. 36.
    Tsuzuki, T., Fujii, Y., Sakumi, K., Tominaga, Y., Nakao, K., Sekiguchi, M., et al. (1996). Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proceedings of the National Academy of Sciences of the United States of America, 93, 6236–6240.PubMedGoogle Scholar
  37. 37.
    Hanada, K., & Hickson, I. D. (2007). Molecular genetics of RecQ helicase disorders. Cellular and Molecular Life Sciences, 64, 2306–2322.PubMedGoogle Scholar
  38. 38.
    Pellegrini, L., & Venkitaraman, A. (2004). Emerging functions of BRCA2 in DNA recombination. Trends in Biochemical Sciences, 29, 310–316.PubMedGoogle Scholar
  39. 39.
    Lee, S. E., Moore, J. K., Holmes, A., Umezu, K., Kolodner, R. D., & Haber, J. E. (1998). Saccharomyces Ku70, mre11/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell, 94, 399–409.PubMedGoogle Scholar
  40. 40.
    Tauchi, H., Kobayashi, J., Morishima, K., van Gent, D. C., Shiraishi, T., Verkaik, N. S., et al. (2002). Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature, 420, 93–98.PubMedGoogle Scholar
  41. 41.
    Limbo, O., Chahwan, C., Yamada, Y., de Bruin, R. A., Wittenberg, C., & Russell, P. (2007). Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Molecular Cell, 28, 134–146.PubMedGoogle Scholar
  42. 42.
    Sartori, A. A., Lukas, C., Coates, J., Mistrik, M., Fu, S., Bartek, J., et al. (2007). Human CtIP promotes DNA end resection. Nature, 450, 509–514.PubMedGoogle Scholar
  43. 43.
    Lusetti, S. L., & Cox, M. M. (2002). The bacterial RecA protein and the recombinational DNA repair of stalled replication forks. Annual Review of Biochemistry, 71, 71–100.PubMedGoogle Scholar
  44. 44.
    Kowalczykowski, S. C., & Krupp, R. A. (1995). DNA-strand exchange promoted by RecA protein in the absence of ATP: implications for the mechanism of energy transduction in protein-promoted nucleic acid transactions. Proceedings of the National Academy of Sciences of the United States of America, 92, 3478–3482.PubMedGoogle Scholar
  45. 45.
    Sung, P., & Stratton, S. A. (1996). Yeast Rad51 recombinase mediates polar DNA strand exchange in the absence of ATP hydrolysis. Journal of Biological Chemistry, 271, 27983–27986.PubMedGoogle Scholar
  46. 46.
    Chi, P., Van Komen, S., Sehorn, M. G., Sigurdsson, S., & Sung, P. (2006). Roles of ATP binding and ATP hydrolysis in human Rad51 recombinase function. DNA Repair, 5, 381–391.PubMedGoogle Scholar
  47. 47.
    Conway, A. B., Lynch, T. W., Zhang, Y., Fortin, G. S., Fung, C. W., Symington, L. S., et al. (2004). Crystal structure of a Rad51 filament. Nature Structural & Molecular Biology, 11, 791–796.Google Scholar
  48. 48.
    Brendel, V., Brocchieri, L., Sandler, S. J., Clark, A. J., & Karlin, S. (1997). Evolutionary comparisons of RecA-like proteins across all major kingdoms of living organisms. Journal of Molecular Evolution, 44, 528–541.PubMedGoogle Scholar
  49. 49.
    Benson, F. E., Stasiak, A., & West, S. C. (1994). Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA. EMBO Journal, 13, 5764–5771.PubMedGoogle Scholar
  50. 50.
    Mameren, J., Modesti, M., Kanaar, R., Wyman, C., Wuite, G. J., & Peterman, E. J. (2006). Dissecting elastic heterogeneity along DNA molecules coated partly with Rad51 using concurrent fluorescence microscopy and optical tweezers. Biophysical Journal, 91, L78–L80.PubMedGoogle Scholar
  51. 51.
    Modesti, M., Ristic, D., van der Heijden, T., Dekker, C., van Mameren, J., Peterman, E. J., et al. (2007). Fluorescent human RAD51 reveals multiple nucleation sites and filament segments tightly associated along a single DNA molecule. Structure, 15, 599–609.PubMedGoogle Scholar
  52. 52.
    Shan, Q., & Cox, M. M. (1997). RecA filament dynamics during DNA strand exchange reactions. Journal of Biological Chemistry, 272, 11063–11073.PubMedGoogle Scholar
  53. 53.
    Shan, Q., & Cox, M. M. (1996). RecA protein dynamics in the interior of RecA nucleoprotein filaments. Journal of Molecular Biology, 257, 756–774.PubMedGoogle Scholar
  54. 54.
    Solinger, J. A., Kiianitsa, K., & Heyer, W. D. (2002). Rad54, a Swi2/Snf2-like recombinational repair protein, disassembles Rad51:dsDNA filaments. Molecular Cell, 10, 1175–1188.PubMedGoogle Scholar
  55. 55.
    Sugawara, N., Wang, X., & Haber, J. E. (2003). In vivo roles of Rad52, Rad54, and Rad55 proteins in Rad51-mediated recombination. Molecular Cell, 12, 209–219.PubMedGoogle Scholar
  56. 56.
    Wittschieben, J. P., Reshmi, S. C., Gollin, S. M., & Wood, R. D. (2006). Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Research, 66, 134–142.PubMedGoogle Scholar
  57. 57.
    Okada, T., Sonoda, E., Yoshimura, M., Kawano, Y., Saya, H., Kohzaki, M., et al. (2005). Multiple roles of vertebrate REV genes in DNA repair and recombination. Molecular and Cellular Biology, 25, 6103–6111.PubMedGoogle Scholar
  58. 58.
    Paques, F., & Haber, J. E. (1999). Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews, 63, 349–404.PubMedGoogle Scholar
  59. 59.
    Szostak, J. W., Orr-Weaver, T. L., Rothstein, R. J., & Stahl, F. W. (1983). The double-strand-break repair model for recombination. Cell, 33, 25–35.PubMedGoogle Scholar
  60. 60.
    West, S. C. (1997). Processing of recombination intermediates by the RuvABC proteins. Annual Review of Genetics, 31, 213–244.PubMedGoogle Scholar
  61. 61.
    Constantinou, A., Davies, A. A., & West, S. C. (2001). Branch migration and Holliday junction resolution catalyzed by activities from mammalian cells. Cell, 104, 259–268.PubMedGoogle Scholar
  62. 62.
    Wu, L., & Hickson, I. D. (2003). The Bloom’s syndrome helicase suppresses crossing over during homologous recombination. Nature, 426, 870–874.PubMedGoogle Scholar
  63. 63.
    Wyman, C., & Kanaar, R. (2006). DNA double-strand break repair: All’s well that ends well. Annual Review of Genetics, 40, 363–383.PubMedGoogle Scholar
  64. 64.
    Sugiyama, T., Zaitseva, E. M., & Kowalczykowski, S. C. (1997). A single-stranded DNA-binding protein is needed for efficient presynaptic complex formation by the Saccharomyces cerevisiae Rad51 protein. Journal of Biological Chemistry, 272, 7940–7945.PubMedGoogle Scholar
  65. 65.
    Esashi, F., Galkin, V. E., Yu, X., Egelman, E. H., & West, S. C. (2007). Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nature Structural & Molecular Biology, 14, 468–474.Google Scholar
  66. 66.
    Modesti, M., Budzowska, M., Baldeyron, C., Demmers, J. A., Ghirlando, R., & Kanaar, R. (2007). RAD51AP1 is a structure-specific DNA binding protein that stimulates joint molecule formation during RAD51-mediated homologous recombination. Molecular Cell, 28, 468–481.PubMedGoogle Scholar
  67. 67.
    Wiese, C., Dray, E., Groesser, T., San Filippo, J., Shi, I., Collins, D. W., et al. (2007). Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement. Molecular Cell, 28, 482–490.PubMedGoogle Scholar
  68. 68.
    Bugreev, D. V., Hanaoka, F., & Mazin, A. V. (2007). Rad54 dissociates homologous recombination intermediates by branch migration. Nature Structural & Molecular Biology, 14, 746–753.Google Scholar
  69. 69.
    Heller, R. C., & Marians, K. J. (2006). Replication fork reactivation downstream of a blocked nascent leading strand. Nature, 439, 557–562.PubMedGoogle Scholar
  70. 70.
    Seigneur, M., Bidnenko, V., Ehrlich, S. D., & Michel, B. (1998). RuvAB acts at arrested replication forks. Cell, 95, 419–430.PubMedGoogle Scholar
  71. 71.
    Hanada, K., Budzowska, M., Modesti, M., Maas, A., Wyman, C., Essers, J., et al. (2006). The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks. EMBO Journal, 25, 4921–4932.PubMedGoogle Scholar
  72. 72.
    Pages, V., & Fuchs, R. P. (2002). How DNA lesions are turned into mutations within cells? Oncogene, 21, 8957–8966.PubMedGoogle Scholar
  73. 73.
    Lehmann, A. R. (2002). Replication of damaged DNA in mammalian cells: New solutions to an old problem. Mutation Research, 509, 23–34.PubMedGoogle Scholar
  74. 74.
    Yang, W. (2003). Damage repair DNA polymerases Y. Current Opinion in Structural Biology, 13, 23–30.PubMedGoogle Scholar
  75. 75.
    Kunkel, T. A., Pavlov, Y. I., & Bebenek, K. (2003). Functions of human DNA polymerases eta, kappa and iota suggested by their properties, including fidelity with undamaged DNA templates. DNA Repair, 2, 135–149.PubMedGoogle Scholar
  76. 76.
    Lawrence, C. (1994). The RAD6 DNA repair pathway in Saccharomyces cerevisiae: What does it do, and how does it do it? Bioessays, 16, 253–258.PubMedGoogle Scholar
  77. 77.
    Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G., & Jentsch, S. (2002). RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature, 419, 135–141.PubMedGoogle Scholar
  78. 78.
    Ulrich, H. D., & Jentsch, S. (2000). Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair. EMBO Journal, 19, 3388–3397.PubMedGoogle Scholar
  79. 79.
    Hofmann, R. M., & Pickart, C. M. (1999). Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell, 96, 645–653.PubMedGoogle Scholar
  80. 80.
    Stelter, P., & Ulrich, H. D. (2003). Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature, 425, 188–191.PubMedGoogle Scholar
  81. 81.
    Bienko, M., Green, C. M., Crosetto, N., Rudolf, F., Zapart, G., Coull, B., et al. (2005). Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science, 310, 1821–1824.PubMedGoogle Scholar
  82. 82.
    Kannouche, P. L., Wing, J., & Lehmann, A. R. (2004). Interaction of human DNA polymerase eta with monoubiquitinated PCNA: A possible mechanism for the polymerase switch in response to DNA damage. Molecular Cell, 14, 491–500.PubMedGoogle Scholar
  83. 83.
    Watanabe, K., Tateishi, S., Kawasuji, M., Tsurimoto, T., Inoue, H., & Yamaizumi, M. (2004). Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO Journal, 23, 3886–3896.PubMedGoogle Scholar
  84. 84.
    Kannouche, P., Fernandez de Henestrosa, A. R., Coull, B., Vidal, A. E., Gray, C., Zicha, D., et al. (2003). Localization of DNA polymerases eta and iota to the replication machinery is tightly co-ordinated in human cells. EMBO Journal, 22, 1223–1233.PubMedGoogle Scholar
  85. 85.
    Bi, X., Barkley, L. R., Slater, D. M., Tateishi, S., Yamaizumi, M., Ohmori, H., et al. (2006). Rad18 regulates DNA polymerase kappa and is required for recovery from S-phase checkpoint-mediated arrest. Molecular and Cellular Biology, 26, 3527–3540.PubMedGoogle Scholar
  86. 86.
    Huang, T. T., Nijman, S. M., Mirchandani, K. D., Galardy, P. J., Cohn, M. A., Haas, W., et al. (2006). Regulation of monoubiquitinated PCNA by DUB autocleavage. Nature Cell Biology, 8, 339–347.PubMedGoogle Scholar
  87. 87.
    Frampton, J., Irmisch, A., Green, C. M., Neiss, A., Trickey, M., Ulrich, H. D., et al. (2006). Postreplication repair and PCNA modification in Schizosaccharomyces pombe. Molecular Biology of the Cell, 17, 2976–2985.PubMedGoogle Scholar
  88. 88.
    Bailly, V., Lauder, S., Prakash, S., & Prakash, L. (1997). Yeast DNA repair proteins Rad6 and Rad18 form a heterodimer that has ubiquitin conjugating, DNA binding, and ATP hydrolytic activities. Journal of Biological Chemistry, 272, 23360–23365.PubMedGoogle Scholar
  89. 89.
    Prakash, S., & Prakash, L. (2002). Translesion DNA synthesis in eukaryotes: A one- or two-polymerase affair. Genes and Development, 16, 1872–1883.PubMedGoogle Scholar
  90. 90.
    Bridges, B. A., & Woodgate, R. (1985). The two-step model of bacterial UV mutagenesis. Mutation Research, 150, 133–139.PubMedGoogle Scholar
  91. 91.
    Guo, C., Tang, T. S., Bienko, M., Parker, J. L., Bielen, A. B., Sonoda, E., et al. (2006). Ubiquitin-binding motifs in REV1 protein are required for its role in the tolerance of DNA damage. Molecular and Cellular Biology, 26, 8892–8900.PubMedGoogle Scholar
  92. 92.
    Ohashi, E., Murakumo, Y., Kanjo, N., Akagi, J., Masutani, C., Hanaoka, F., et al. (2004). Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells, 9, 523–531.PubMedGoogle Scholar
  93. 93.
    Guo, C., Fischhaber, P. L., Luk-Paszyc, M. J., Masuda, Y., Zhou, J., Kamiya, K., et al. (2003). Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. EMBO Journal, 22, 6621–6630.PubMedGoogle Scholar
  94. 94.
    Tissier, A., Kannouche, P., Reck, M. P., Lehmann, A. R., Fuchs, R. P., & Cordonnier, A. (2004). Co-localization in replication foci and interaction of human Y-family members, DNA polymerase pol eta and REVl protein. DNA Repair, 3, 1503–1514.PubMedGoogle Scholar
  95. 95.
    Masutani, C., Kusumoto, R., Iwai, S., & Hanaoka, F. (2000). Mechanisms of accurate translesion synthesis by human DNA polymerase eta. EMBO Journal, 19, 3100–3109.PubMedGoogle Scholar
  96. 96.
    Chiu, R. K., Brun, J., Ramaekers, C., Theys, J., Weng, L., Lambin, P., et al. (2006). Lysine 63-polyubiquitination guards against translesion synthesis-induced mutations. PLoS Genetics, 2, e116.PubMedGoogle Scholar
  97. 97.
    Langie, S. A., Knaapen, A. M., Ramaekers, C. H., Theys, J., Brun, J., Godschalk, R. W., et al. (2007). Formation of lysine 63-linked poly-ubiquitin chains protects human lung cells against benzo[a]pyrene-diol-epoxide-induced mutagenicity. DNA Repair, 6, 852–862.PubMedGoogle Scholar
  98. 98.
    Courcelle, J., Khodursky, A., Peter, B., Brown, P. O., & Hanawalt, P. C. (2001). Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli. Genetics, 158, 41–64.PubMedGoogle Scholar
  99. 99.
    Sutton, M. D., & Walker, G. C. (2001). Managing DNA polymerases: Coordinating DNA replication, DNA repair, and DNA recombination. Proceedings of the National Academy of Sciences of the United States of America, 98, 8342–8349.PubMedGoogle Scholar
  100. 100.
    Tang, M., Bruck, I., Eritja, R., Turner, J., Frank, E. G., Woodgate, R., et al. (1998). Biochemical basis of SOS-induced mutagenesis in Escherichia coli: Reconstitution of in vitro lesion bypass dependent on the UmuD’2C mutagenic complex and RecA protein. Proceedings of the National Academy of Sciences of the United States of America, 95, 9755–9760.PubMedGoogle Scholar
  101. 101.
    Reuven, N. B., Arad, G., Maor-Shoshani, A., & Livneh, Z. (1999). The mutagenesis protein UmuC is a DNA polymerase activated by UmuD’, RecA, and SSB and is specialized for translesion replication. Journal of Biological Chemistry, 274, 31763–31766.PubMedGoogle Scholar
  102. 102.
    Schlacher, K., Cox, M. M., Woodgate, R., & Goodman, M. F. (2006). RecA acts in trans to allow replication of damaged DNA by DNA polymerase V. Nature, 442, 883–887.PubMedGoogle Scholar
  103. 103.
    Sommer, S., Bailone, A., & Devoret, R. (1993). The appearance of the UmuD’C protein complex in Escherichia coli switches repair from homologous recombination to SOS mutagenesis. Molecular Microbiology, 10, 963–971.PubMedGoogle Scholar
  104. 104.
    Rehrauer, W. M., Bruck, I., Woodgate, R., Goodman, M. F., & Kowalczykowski, S. C. (1998). Modulation of RecA nucleoprotein function by the mutagenic UmuD’C protein complex. Journal of Biological Chemistry, 273, 32384–32387.PubMedGoogle Scholar
  105. 105.
    Opperman, T., Murli, S., Smith, B. T., & Walker, G. C. (1999). A model for a umuDC-dependent prokaryotic DNA damage checkpoint. Proceedings of the National Academy of Sciences of the United States of America, 96, 9218–9223.PubMedGoogle Scholar
  106. 106.
    Tanner, N. A., Hamdan, S. M., Jergic, S., Schaeffer, P. M., Dixon, N. E., & van Oijen, A. M. (2008). Single-molecule studies of fork dynamics in Escherichia coli DNA replication. Nature Structural & Molecular Biology, 15, 170–176.Google Scholar
  107. 107.
    Lukas, C., Falck, J., Bartkova, J., Bartek, J., & Lukas, J. (2003). Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage. Nature Cell Biology, 5, 255–260.PubMedGoogle Scholar
  108. 108.
    Yagi, Y., Ogawara, D., Iwai, S., Hanaoka, F., Akiyama, M., & Maki, H. (2005). DNA polymerases eta and kappa are responsible for error-free translesion DNA synthesis activity over a cis-syn thymine dimer in Xenopus laevis oocyte extracts. DNA Repair, 4, 1252–1269.PubMedGoogle Scholar
  109. 109.
    Lehmann, A. R., Kirk-Bell, S., Arlett, C. F., Paterson, M. C., Lohman, P. H., de Weerd-Kastelein, E. A., et al. (1975). Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation. Proceedings of the National Academy of Sciences of the United States of America, 72, 219–223.PubMedGoogle Scholar
  110. 110.
    Kannouche, P., Broughton, B. C., Volker, M., Hanaoka, F., Mullenders, L. H., & Lehmann, A. R. (2001). Domain structure, localization, and function of DNA polymerase eta, defective in xeroderma pigmentosum variant cells. Genes and Development, 15, 158–172.PubMedGoogle Scholar
  111. 111.
    McIlwraith, M. J., Vaisman, A., Liu, Y., Fanning, E., Woodgate, R., & West, S. C. (2005). Human DNA polymerase eta promotes DNA synthesis from strand invasion intermediates of homologous recombination. Molecular Cell, 20, 783–792.PubMedGoogle Scholar
  112. 112.
    Kawamoto, T., Araki, K., Sonoda, E., Yamashita, Y. M., Harada, K., Kikuchi, K., et al. (2005). Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Molecular Cell, 20, 793–799.PubMedGoogle Scholar
  113. 113.
    Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S., & Prakash, L. (2000). Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature, 406, 1015–1019.PubMedGoogle Scholar
  114. 114.
    Zhang, Y., Wu, X., Guo, D., Rechkoblit, O., & Wang, Z. (2002). Activities of human DNA polymerase kappa in response to the major benzo[a]pyrene DNA adduct: Error-free lesion bypass and extension synthesis from opposite the lesion. DNA Repair, 1, 559–569.PubMedGoogle Scholar
  115. 115.
    Suzuki, N., Ohashi, E., Kolbanovskiy, A., Geacintov, N. E., Grollman, A. P., Ohmori, H., et al. (2002). Translesion synthesis by human DNA polymerase kappa on a DNA template containing a single stereoisomer of dG-(+)- or dG-(-)-anti-N(2)-BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene). Biochemistry, 41, 6100–6106.PubMedGoogle Scholar
  116. 116.
    Ogi, T., Shinkai, Y., Tanaka, K., & Ohmori, H. (2002). Polkappa protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene. Proceedings of the National Academy of Sciences of the United States of America, 99, 15548–15553.PubMedGoogle Scholar
  117. 117.
    Ogi, T., Kannouche, P., & Lehmann, A. R. (2005). Localisation of human Y-family DNA polymerase kappa: Relationship to PCNA foci. Journal of Cell Science, 118, 129–136.PubMedGoogle Scholar
  118. 118.
    Nelson, J. R., Lawrence, C. W., & Hinkle, D. C. (1996). Deoxycytidyl transferase activity of yeast REV1 protein. Nature, 382, 729–731.PubMedGoogle Scholar
  119. 119.
    Nelson, J. R., Lawrence, C. W., & Hinkle, D. C. (1996). Thymine-thymine dimer bypass by yeast DNA polymerase zeta. Science, 272, 1646–1649.PubMedGoogle Scholar
  120. 120.
    Lambert, S., & Carr, A. M. (2005). Checkpoint responses to replication fork barriers. Biochimie, 87, 591–602.PubMedGoogle Scholar
  121. 121.
    Unsal-Kacmaz, K., Chastain, P. D., Qu, P. P., Minoo, P., Cordeiro-Stone, M., Sancar, A., et al. (2007). The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Molecular and Cellular Biology, 27, 3131–3142.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  1. 1.Department of Cell Biology & GeneticsCancer Genomics CenterRotterdamThe Netherlands
  2. 2.Department of Radiation OncologyErasmus Medical CenterRotterdamThe Netherlands

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