Advertisement

Regulation of the Initiation of DNA Replication upon DNA Damage in Eukaryotes

  • Kerstin Köhler
  • Pedro Ferreira
  • Boris Pfander
  • Dominik Boos
Chapter

Abstract

Cycling cells must ensure homeostasis of the genetic information during repeated chromosome replication-segregation cycles. To guarantee genome stability in normal and DNA damage conditions the initiation of DNA replication in eukaryotes is regulated by the cell cycle machinery and the intra S-phase checkpoint (ISC). The cell cycle kinases CDK and DDK induce initiation specifically in S phase, and the ISC inhibits both kinase pathways, suppressing initiation upon DNA damage and replisome stalling to prevent the replication machinery from having to copy damaged DNA templates. Despite this ISC-mediated inhibition, dormant origins are allowed to fire in genomic regions that are actively engaged in replication when the DNA damage occurs. Forks from dormant origins can rescue replisomes that have stalled at DNA lesions, helping to ensure that no part of these replicating regions is left unreplicated in DNA damage conditions. This replisome rescue also helps prevent stalled and collapsed forks from causing genome rearrangements. In higher eukaryotes, these principles of regulating initiation upon DNA damage must be implemented into a particularly complex temporal regulation programme of genome replication. Molecular details of how the ISC, which poses an important barrier against tumour formation, achieves the regulation of initiation upon DNA damage is only beginning to emerge.

Keywords

Intra S-phase checkpoint (ISC) Initiation of DNA replication DNA damage Replisome stalling Radio-resistant DNA synthesis (RDS) CDK DDK ATR CHK1 Sld3 Treslin/TICRR Sld2 Dpb11 TopBP1 

Notes

Acknowledgements

We are grateful to Belen Gomez Gonzales, Juliane Pfrötzschner, Jenny Bormann, Melisa Merdanovic, Gerben Vader and the members of the Pfander lab for helpful discussions and critical reading of the manuscript. The lab of D. Boos is supported by an NRW Rückkehrerförderprogramm fellowship from the Ministry for Innovation, Science and Research of North Rhine-Westphalia, Germany. The Pfander lab is supported by the Max-Planck Society and the German Research Council (DFG). The authors declare that they have no competing financial interest.

References

  1. 1.
    Lopes M, et al. The DNA replication checkpoint response stabilizes stalled replication forks. Nature. 2001;412(6846):557–61.CrossRefPubMedGoogle Scholar
  2. 2.
    Tercero JA, Diffley JFX. Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature. 2001;412(6846):553–7.CrossRefPubMedGoogle Scholar
  3. 3.
    McIntosh D, Blow JJ. Dormant origins, the licensing checkpoint, and the response to replicative stresses. Cold Spring Harb Perspect Biol. 2012;4(10):012955.CrossRefGoogle Scholar
  4. 4.
    Santocanale C, Diffley JFX. A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature. 1998;395(6702):615–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Shirahige K, et al. Regulation of DNA-replication origins during cell-cycle progression. Nature. 1998;395(6702):618–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem. 2002;71:333–74.CrossRefPubMedGoogle Scholar
  7. 7.
    Boos D, Frigola J, Diffley JFX. Activation of the replicative DNA helicase: breaking up is hard to do. Curr Opin Cell Biol. 2012;24(3):423–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Diffley JFX. Regulation of early events in chromosome replication. Curr Biol. 2004;14(18):R778–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Flynn RL, Zou L. ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci. 2011;36(3):133–40.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Walter J, Newport J. Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha. Mol Cell. 2000;5(4):617–27.CrossRefPubMedGoogle Scholar
  11. 11.
    Pacek M, Walter JC. A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication. EMBO J. 2004;23(18):3667–76.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Byun TS, et al. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19(9):1040–52.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Pacek M, et al. Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Mol Cell. 2006;21(4):581–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Painter RB. Inhibition of initiation of HeLa cell replicons by methyl methanesulfonate. Mutat Res. 1977;42(2):299–303.CrossRefPubMedGoogle Scholar
  15. 15.
    Painter RB. Inhibition and recovery of DNA synthesis in human cells after exposure to ultraviolet light. Mutat Res. 1985;145(1-2):63–9.PubMedGoogle Scholar
  16. 16.
    Painter RB, Young BR. Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci U S A. 1980;77(12):7315–7.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Larner JM, et al. Radiation down-regulates replication origin activity throughout the S phase in mammalian cells. Nucleic Acids Res. 1999;27(3):803–9.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Lee H, Larner JM, Hamlin JL. A p53-independent damage-sensing mechanism that functions as a checkpoint at the G1/S transition in Chinese hamster ovary cells. Proc Natl Acad Sci U S A. 1997;94(2):526–31.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Yekezare M, Gomez-Gonzalez B, Diffley JF. Controlling DNA replication origins in response to DNA damage – inhibit globally, activate locally. J Cell Sci. 2013;126(Pt 6):1297–306.CrossRefPubMedGoogle Scholar
  20. 20.
    Bartkova J, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434(7035):864–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Bartkova J, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Di Micco R, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444(7119):638–42.CrossRefPubMedGoogle Scholar
  23. 23.
    Gorgoulis VG, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434(7035):907–13.CrossRefPubMedGoogle Scholar
  24. 24.
    Paulovich AG, Hartwell LH. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell. 1995;82(5):841–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Yoshida K, Poveda A, Pasero P. Time to be versatile: regulation of the replication timing program in budding yeast. J Mol Biol. 2013;425(23):4696–705.CrossRefPubMedGoogle Scholar
  26. 26.
    Santocanale C, Sharma K, Diffley JFX. Activation of dormant origins of DNA replication in budding yeast. Genes Dev. 1999;13(18):2360–4.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Zegerman P, Diffley JFX. Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature. 2007;445(7125):281–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Tanaka S, et al. CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature. 2007;445(7125):328–32.CrossRefPubMedGoogle Scholar
  29. 29.
    Sheu YJ, Stillman B. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature. 2010;463(7277):113–7.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Zegerman P, Diffley JFX. Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation. Nature. 2010;467(7314):474–8.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Lopez-Mosqueda J, et al. Damage-induced phosphorylation of Sld3 is important to block late origin firing. Nature. 2010;467(7314):479–83.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Duch A, et al. A Dbf4 mutant contributes to bypassing the Rad53-mediated block of origins of replication in response to genotoxic stress. J Biol Chem. 2011;286(4):2486–91.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Boos D, et al. Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. Curr Biol. 2011;21(13):1152–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Kumagai A, Shevchenko A, Dunphy WG. Direct regulation of Treslin by cyclin-dependent kinase is essential for the onset of DNA replication. J Cell Biol. 2011;193(6):995–1007.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Gaggioli V, et al. CDK phosphorylation of SLD-2 is required for replication initiation and germline development in C. elegans. J Cell Biol. 2014;204(4):507–22.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Matsuno K, et al. The N-terminal noncatalytic region of Xenopus RecQ4 is required for chromatin binding of DNA polymerase alpha in the initiation of DNA replication. Mol Cell Biol. 2006;26(13):4843–52.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Kumagai A, Shevchenko A, Dunphy WG. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication. Cell. 2010;140(3):349–59.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Sansam CL, et al. A vertebrate gene, ticrr, is an essential checkpoint and replication regulator. Genes Dev. 2010;24(2):183–94.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Mailand N, et al. Rapid destruction of human Cdc25A in response to DNA damage. Science. 2000;288(5470):1425–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Molinari M, et al. Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep. 2000;1(1):71–9.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Hughes BT, et al. Essential role for Cdk2 inhibitory phosphorylation during replication stress revealed by a human Cdk2 knockin mutation. Proc Natl Acad Sci U S A. 2013;110(22):8954–9.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Falck J, et al. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature. 2001;410(6830):842–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Busino L, et al. Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature. 2003;426(6962):87–91.CrossRefPubMedGoogle Scholar
  44. 44.
    McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998;93(6):1043–53.CrossRefPubMedGoogle Scholar
  45. 45.
    Arias EE, Walter JC. Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. Genes Dev. 2005;19(1):114–26.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Arias EE, Walter JC. PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication. Nat Cell Biol. 2006;8(1):84–90.CrossRefPubMedGoogle Scholar
  47. 47.
    Guo C, et al. Interaction of Chk1 with Treslin negatively regulates the initiation of chromosomal DNA replication. Mol Cell. 2014;57(3):492–505.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Roberts BT, et al. DNA replication in vertebrates requires a homolog of the Cdc7 protein kinase. Proc Natl Acad Sci U S A. 1999;96(6):2800–4.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Walter JC. Evidence for sequential action of cdc7 and cdk2 protein kinases during initiation of DNA replication in Xenopus egg extracts. J Biol Chem. 2000;275(50):39773–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Costanzo V, et al. An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol Cell. 2003;11(1):203–13.CrossRefPubMedGoogle Scholar
  51. 51.
    Poh WT, et al. Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated protein phosphatase 1. Open Biol. 2014;4:130138.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Tsuji T, et al. The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control. Mol Cell. 2008;32(6):862–9.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Heffernan TP, et al. Cdc7-Dbf4 and the human S checkpoint response to UVC. J Biol Chem. 2007;282(13):9458–68.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Tenca P, et al. Cdc7 is an active kinase in human cancer cells undergoing replication stress. J Biol Chem. 2007;282(1):208–15.CrossRefPubMedGoogle Scholar
  55. 55.
    Silva T, et al. Xenopus CDC7/DRF1 complex is required for the initiation of DNA replication. J Biol Chem. 2006;281(17):11569–76.CrossRefPubMedGoogle Scholar
  56. 56.
    Petersen P, et al. Protein phosphatase 2A antagonizes ATM and ATR in a Cdk2- and Cdc7-independent DNA damage checkpoint. Mol Cell Biol. 2006;26(5):1997–2011.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Liu P, et al. The Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism. J Biol Chem. 2006;281(41):30631–44.CrossRefPubMedGoogle Scholar
  58. 58.
    Dimitrova DS, Gilbert DM. The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol Cell. 1999;4(6):983–93.CrossRefPubMedGoogle Scholar
  59. 59.
    Berezney R, Dubey DD, Huberman JA. Heterogeneity of eukaryotic replicons, replicon clusters, and replication foci. Chromosoma. 2000;108(8):471–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Leonhardt H, et al. Dynamics of DNA replication factories in living cells. J Cell Biol. 2000;149(2):271–80.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Hiratani I, et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 2008;6(10), e245.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Ryba T, et al. Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res. 2010;20(6):761–70.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Ge XQ, Jackson DA, Blow JJ. Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes Dev. 2007;21(24):3331–41.PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Woodward AM, et al. Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol. 2006;173(5):673–83.PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Anglana M, et al. Dynamics of DNA replication in mammalian somatic cells: nucleotide pool modulates origin choice and interorigin spacing. Cell. 2003;114(3):385–94.CrossRefPubMedGoogle Scholar
  66. 66.
    Courbet S, et al. Replication fork movement sets chromatin loop size and origin choice in mammalian cells. Nature. 2008;455(7212):557–60.CrossRefPubMedGoogle Scholar
  67. 67.
    Desany BA, et al. Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway. Genes Dev. 1998;12(18):2956–70.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Shima N, et al. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet. 2007;39(1):93–8.CrossRefPubMedGoogle Scholar
  69. 69.
    Glover TW, et al. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet. 1984;67(2):136–42.CrossRefPubMedGoogle Scholar
  70. 70.
    Casper AM, et al. ATR regulates fragile site stability. Cell. 2002;111(6):779–89.CrossRefPubMedGoogle Scholar
  71. 71.
    Letessier A, et al. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature. 2011;470(7332):120–3.CrossRefPubMedGoogle Scholar
  72. 72.
    Ozeri-Galai E, et al. Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites. Mol Cell. 2011;43(1):122–31.CrossRefPubMedGoogle Scholar
  73. 73.
    Dimitrova DS, Gilbert DM. Temporally coordinated assembly and disassembly of replication factories in the absence of DNA synthesis. Nat Cell Biol. 2000;2(10):686–94.PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Ge XQ, Blow JJ. Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories. J Cell Biol. 2010;191(7):1285–97.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Thomson AM, Gillespie PJ, Blow JJ. Replication factory activation can be decoupled from the replication timing program by modulating Cdk levels. J Cell Biol. 2010;188(2):209–21.PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Mantiero D, et al. Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J. 2011;30(23):4805–14.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Tanaka S, et al. Origin association of Sld3, Sld7, and Cdc45 proteins is a key step for determination of origin-firing timing. Curr Biol. 2011;21(24):2055–63.CrossRefPubMedGoogle Scholar
  78. 78.
    Collart C, et al. Titration of four replication factors is essential for the Xenopus laevis midblastula transition. Science. 2013;341(6148):893–6.PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Trenz K, Errico A, Costanzo V. Plx1 is required for chromosomal DNA replication under stressful conditions. EMBO J. 2008;27(6):876–85.PubMedCentralCrossRefPubMedGoogle Scholar
  80. 80.
    Yoo HY, et al. Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell. 2004;117(5):575–88.CrossRefPubMedGoogle Scholar
  81. 81.
    Donnianni RA, et al. Elevated levels of the polo kinase Cdc5 override the Mec1/ATR checkpoint in budding yeast by acting at different steps of the signaling pathway. PLoS Genet. 2010;6(1), e1000763.PubMedCentralCrossRefPubMedGoogle Scholar
  82. 82.
    Chou DM, et al. Protein phosphatase 2A regulates binding of Cdc45 to the prereplication complex. J Biol Chem. 2002;277(43):40520–7.CrossRefPubMedGoogle Scholar
  83. 83.
    Chen YH, et al. ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Mol Cell. 2015;58(2):323–38.CrossRefPubMedGoogle Scholar
  84. 84.
    Yoo HY, et al. Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses. J Biol Chem. 2004;279(51):53353–64.CrossRefPubMedGoogle Scholar
  85. 85.
    Song B, et al. Plk1 phosphorylation of Orc2 promotes DNA replication under conditions of stress. Mol Cell Biol. 2011;31(23):4844–56.PubMedCentralCrossRefPubMedGoogle Scholar
  86. 86.
    Peschiaroli A, et al. SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol Cell. 2006;23(3):319–29.CrossRefPubMedGoogle Scholar
  87. 87.
    Mamely I, et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol. 2006;16(19):1950–5.CrossRefPubMedGoogle Scholar
  88. 88.
    Mailand N, et al. Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol Cell. 2006;23(3):307–18.CrossRefPubMedGoogle Scholar
  89. 89.
    Hiraga S, et al. Rif1 controls DNA replication by directing protein phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes Dev. 2014;28(4):372–83.PubMedCentralCrossRefPubMedGoogle Scholar
  90. 90.
    Mattarocci S, et al. Rif1 controls DNA replication timing in yeast through the PP1 phosphatase Glc7. Cell Rep. 2014;7(1):62–9.CrossRefPubMedGoogle Scholar
  91. 91.
    Dave A, et al. Protein phosphatase 1 recruitment by Rif1 regulates DNA replication origin firing by counteracting DDK activity. Cell Rep. 2014;7(1):53–61.PubMedCentralCrossRefPubMedGoogle Scholar
  92. 92.
    Tazumi A, et al. Telomere-binding protein Taz1 controls global replication timing through its localization near late replication origins in fission yeast. Genes Dev. 2012;26(18):2050–62.PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Yamazaki S, et al. Rif1 regulates the replication timing domains on the human genome. EMBO J. 2012;31(18):3667–77.PubMedCentralCrossRefPubMedGoogle Scholar
  94. 94.
    Cornacchia D, et al. Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J. 2012;31(18):3678–90.PubMedCentralCrossRefPubMedGoogle Scholar
  95. 95.
    Sheu YJ, Stillman B. Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell. 2006;24(1):101–13.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Kerstin Köhler
    • 1
  • Pedro Ferreira
    • 1
  • Boris Pfander
    • 2
  • Dominik Boos
    • 1
  1. 1.Molecular Genetics II, Vertebrate DNA Replication, Centre for Medical Biotechnology (ZMB)University of Duisburg-EssenEssenGermany
  2. 2.DNA Replication and Genome IntegrityMax-Planck Institute of BiochemistryMartinsriedGermany

Personalised recommendations