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Replication licensing and cancer — a fatal entanglement?

Nature Reviews Cancer volume 8, pages 799–806 (2008)Cite this article

Abstract

Correct regulation of the replication licensing system ensures that chromosomal DNA is precisely duplicated in each cell division cycle. Licensing proteins are inappropriately expressed at an early stage of tumorigenesis in a wide variety of cancers. Here we discuss evidence that misregulation of replication licensing is a consequence of oncogene-induced cell proliferation. This misregulation can cause either under- or over-replication of chromosomal DNA, and could explain the genetic instability commonly seen in cancer cells.

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Figure 1: Overview of origin licensing during the cell division cycle.
Figure 2: Minichromosome maintenance 5 (MCM5) in normal and dysplastic cervical epithelium.
Figure 3: The DNA damage response.
Figure 4: Consequences of re-replication.
Figure 5: Dormant origins and replication fork stalling.

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References

  1. Nishitani, H. & Lygerou, Z. DNA replication licensing. Front. Biosci. 9, 2115–2132 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Blow, J. J. & Dutta, A. Preventing re-replication of chromosomal DNA. Nature Rev. Mol. Cell. Biol. 6, 476–486 (2005).

    Article  CAS  Google Scholar 

  3. Arias, E. E. & Walter, J. C. Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. Genes Dev. 21, 497–518 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Labib, K. & Diffley, J. F. Is the MCM2–7 complex the eukaryotic DNA replication fork helicase? Curr. Opin. Genet. Dev. 11, 64–70 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Moyer, S. E., Lewis, P. W. & Botchan, M. R. Isolation of the Cdc45/Mcm2–7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase. Proc. Natl Acad. Sci. USA 103, 10236–10241 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gillespie, P. J., Li, A. & Blow, J. J. Reconstitution of licensed replication origins on Xenopus sperm nuclei using purified proteins. BMC Biochem. 2, 15 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Perkins, G. & Diffley, J. F. Nucleotide-dependent prereplicative complex assembly by Cdc6p, a homolog of eukaryotic and prokaryotic clamp-loaders. Mol. Cell 2, 23–32 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Nishitani, H., Taraviras, S., Lygerou, Z. & Nishimoto, T. The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S.-phase. J. Biol. Chem. 276, 44905–44911 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Li, X., Zhao, Q., Liao, R., Sun, P. & Wu, X. The SCFSkp2 ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. J. Biol. Chem. 278, 30854–30858 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Zhong, W., Feng, H., Santiago, F. E. & Kipreos, E. T. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature 423, 885–889 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Arias, E. E. & Walter, J. C. PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication. Nature Cell Biol. 8, 84–90 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. McGarry, T. J. & Kirschner, M. W. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 93, 1043–1053 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Tada, S., Li, A., Maiorano, D., Mechali, M. & Blow, J. J. Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin. Nature Cell Biol. 3, 107–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Wohlschlegel, J. A. et al. Inhibition of eukaryotic replication by geminin binding to Cdt1. Science 290, 2309–2312 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Mihaylov, I. S. et al. Control of DNA replication and chromosome ploidy by geminin and cyclin A. Mol. Cell. Biol. 22, 1868–1880 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vaziri, C. et al. A p53-dependent checkpoint pathway prevents rereplication. Mol. Cell 11, 997–1008 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Melixetian, M. et al. Loss of Geminin induces rereplication in the presence of functional p53. J. Cell Biol. 165, 473–482 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thomer, M., May, N. R., Aggarwal, B. D., Kwok, G. & Calvi, B. R. Drosophila double-parked is sufficient to induce re-replication during development and is regulated by cyclin E/CDK2. Development 131, 4807–4818 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Arias, E. E. & Walter, J. C. Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. Genes Dev. 19, 114–126 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li, A. & Blow, J. J. Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus. EMBO J. 24, 395–404 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Zhu, W., Chen, Y. & Dutta, A. Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint. Mol. Cell. Biol. 24, 7140–7150 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stoeber, K. et al. DNA replication licensing and human cell proliferation. J. Cell Sci. 114, 2027–2041 (2001).

    CAS  PubMed  Google Scholar 

  23. Blow, J. J. & Hodgson, B. Replication licensing: defining the proliferative state? Trends Cell Biol. 12, 72–78 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gonzalez, M. A., Tachibana, K. E., Laskey, R. A. & Coleman, N. Control of DNA replication and its potential clinical exploitation. Nature Rev. Cancer 5, 135–141 (2005).

    Article  CAS  Google Scholar 

  25. Hook, S. S., Lin, J. J. & Dutta, A. Mechanisms to control rereplication and implications for cancer. Curr. Opin. Cell Biol. 19, 663–671 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Williams, G. H. & Stoeber, K. Cell cycle markers in clinical oncology. Curr. Opin. Cell Biol. 19, 672–679 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Williams, G. H. et al. Improved cervical smear assessment using antibodies against proteins that regulate DNA replication. Proc. Natl Acad. Sci. USA 95, 14932–14937 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xouri, G. et al. Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. Eur. J. Biochem. 271, 3368–3378 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Lau, E., Tsuji, T., Guo, L., Lu, S. H. & Jiang, W. The role of pre-replicative complex (pre-RC) components in oncogenesis. FASEB J. 21, 3786–3794 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Hu, J., McCall, C. M., Ohta, T. & Xiong, Y. Targeted ubiquitination of CDT1 by the DDB1–CUL4A–ROC1 ligase in response to DNA damage. Nature Cell Biol. 6, 1003–1009 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Hu, J. & Xiong, Y. An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4–Ddb1 ubiquitin ligase in response to DNA damage. J. Biol. Chem. 281, 3753–3756 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Jin, J., Arias, E. E., Chen, J., Harper, J. W. & Walter, J. C. A family of diverse Cul4–Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol. Cell 23, 709–721 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Lovejoy, C. A., Lock, K., Yenamandra, A. & Cortez, D. DDB1 maintains genome integrity through regulation of Cdt1. Mol. Cell. Biol. 26, 7977–7990 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nishitani, H. et al. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J. 25, 1126–1136 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ralph, E., Boye, E. & Kearsey, S. E. DNA damage induces Cdt1 proteolysis in fission yeast through a pathway dependent on Cdt2 and Ddb1. EMBO Rep. 7, 1134–1139 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sansam, C. L. et al. DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes Dev. 20, 3117–3129 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Senga, T. et al. PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J. Biol. Chem. 281, 6246–6252 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, E., Li, X., Yan, F., Zhao, Q. & Wu, X. Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation. J. Biol. Chem. 279, 17283–17288 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Sugimoto, N. et al. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J. Biol. Chem. 279, 19691–19697 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Takeda, D. Y., Parvin, J. D. & Dutta, A. Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S. phase. J. Biol. Chem. 280, 23416–23423 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Sugimoto, N. et al. Identification of novel human Cdt1-binding proteins by a proteomics approach: proteolytic regulation by APC/CCdh1. Mol. Biol. Cell 19, 1007–1021 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hodgson, B., Li, A., Tada, S. & Blow, J. J. Geminin becomes activated as an inhibitor of Cdt1/RLF-B following nuclear import. Curr. Biol. 12, 678–683 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li, A. & Blow, J. J. Non-proteolytic inactivation of geminin requires CDK-dependent ubiquitination. Nature Cell Biol. 6, 260–267 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Quinn, L. M., Herr, A., McGarry, T. J. & Richardson, H. The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis. Genes Dev. 15, 2741–2754 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Di Fiore, B. & Pines, J. Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C. J. Cell Biol. 177, 425–437 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Machida, Y. J. & Dutta, A. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 21, 184–194 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sivaprasad, U., Machida, Y. J. & Dutta, A. APC/C — the master controller of origin licensing? Cell Div. 2, 8 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Lehman, N. L., Verschuren, E. W., Hsu, J. Y., Cherry, A. M. & Jackson, P. K. Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle 5, 1569–1573 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Verschuren, E. W., Ban, K. H., Masek, M. A., Lehman, N. L. & Jackson, P. K. Loss of Emi1-dependent anaphase-promoting complex/cyclosome inhibition deregulates E2F target expression and elicits DNA damage-induced senescence. Mol. Cell. Biol. 27, 7955–7965 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DePamphilis, M. L. et al. Regulating the licensing of DNA replication origins in metazoa. Curr. Opin. Cell Biol. 18, 231–239 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Petersen, B. O., Lukas, J., Sorensen, C. S., Bartek, J. & Helin, K. Phosphorylation of mammalian CDC6 by Cyclin A/CDK2 regulates its subcellular localization. EMBO J. 18, 396–410 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Saha, P. et al. Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. Mol. Cell. Biol. 18, 2758–2767 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alexandrow, M. G. & Hamlin, J. L. Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A. Mol. Cell. Biol. 24, 1614–1627 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim, J., Feng, H. & Kipreos, E. T. C. elegans CUL-4 prevents rereplication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway. Curr. Biol. 17, 966–972 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liontos, M. et al. Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. Cancer Res. 67, 10899–10909 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Petersen, B. O. et al. Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. Genes Dev. 14, 2330–2343 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nishitani, H., Lygerou, Z., Nishimoto, T. & Nurse, P. The Cdt1 protein is required to license DNA for replication in fission yeast. Nature 404, 625–628 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Davidson, I. F., Li, A. & Blow, J. J. Deregulated replication licensing causes DNA fragmentation consistent with head-to-tail fork collision. Mol. Cell 24, 433–443 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhu, W. & Dutta, A. An ATR- and BRCA1-mediated Fanconi anemia pathway is required for activating the G2/M checkpoint and DNA damage repair upon rereplication. Mol. Cell. Biol. 26, 4601–4611 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Green, B. M. & Li, J. J. Loss of rereplication control in Saccharomyces cerevisiae results in extensive DNA damage. Mol. Biol. Cell 16, 421–432 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Arentson, E. et al. Oncogenic potential of the DNA replication licensing protein CDT1. Oncogene 21, 1150–1158 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Gonzalez, S. et al. Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Nature 440, 702–706 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Seo, J. et al. Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53. Oncogene 24, 8176–8186 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Murakami, H., Yanow, S. K., Griffiths, D., Nakanishi, M. & Nurse, P. Maintenance of replication forks and the S-phase checkpoint by Cdc18p and Orp1p. Nature Cell Biol. 4, 384–388 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Clay-Farrace, L., Pelizon, C., Santamaria, D., Pines, J. & Laskey, R. A. Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1. EMBO J. 22, 704–712 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Oehlmann, M., Score, A. J. & Blow, J. J. The role of Cdc6 in ensuring complete genome licensing and S phase checkpoint activation. J. Cell Biol. 165, 181–190 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hermand, D. & Nurse, P. Cdc18 enforces long-term maintenance of the S phase checkpoint by anchoring the Rad3–Rad26 complex to chromatin. Mol. Cell 26, 553–563 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Kan, Q., Jinno, S., Kobayashi, K., Yamamoto, H. & Okayama, H. CDC6 determines utilization of p21WAF1/CIP1-dependent damage checkpoint in S phase cells. J. Biol. Chem. (2008).

  69. Borlado, L. R. & Mendez, J. CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. Carcinogenesis 29, 237–243 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Blow, J. J. & Tanaka, T. U. The chromosome cycle: coordinating replication and segregation. Second in the cycles review series. EMBO Rep. 6, 1028–1034 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Aggarwal, P. et al. Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev. 21, 2908–2922 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Di Micco, R., Fumagalli, M. & d'Adda di Fagagna, F. Breaking news: high-speed race ends in arrest — how oncogenes induce senescence. Trends Cell Biol. 17, 529–536 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Chong, J. P., Mahbubani, H. M., Khoo, C. Y. & Blow, J. J. Purification of an MCM-containing complex as a component of the DNA replication licensing system. Nature 375, 418–421 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Kubota, Y., Mimura, S., Nishimoto, S., Takisawa, H. & Nojima, H. Identification of the yeast MCM3-related protein as a component of Xenopus DNA replication licensing factor. Cell 81, 601–609 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Madine, M. A., Khoo, C.-Y., Mills, A. D. & Laskey, R. A. MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells. Nature 375, 421–424 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Ekholm-Reed, S. et al. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J. Cell Biol. 165, 789–800 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tsuji, T., Ficarro, S. B. & Jiang, W. Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells. Mol. Biol. Cell 17, 4459–4472 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Stuermer, A. et al. Mouse pre-replicative complex proteins colocalise and interact with the centrosome. Eur. J. Cell Biol. 86, 37–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Lambert, S. & Carr, A. M. Checkpoint responses to replication fork barriers. Biochimie 87, 591–602 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Coxon, A., Maundrell, K. & Kearsey, S. E. Fission yeast cdc21+ belongs to a family of proteins involved in an early step of chromosome replication. Nucleic Acids Res. 20, 5571–5577 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lei, M., Kawasaki, Y. & Tye, B. K. Physical interactions among Mcm proteins and effects of Mcm dosage on DNA replication in Saccharomyces cerevisiae. Mol. Cell. Biol. 16, 5081–5090 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liang, D. T., Hodson, J. A. & Forsburg, S. L. Reduced dosage of a single fission yeast MCM protein causes genetic instability and S phase delay. J. Cell Sci. 112, 559–567 (1999).

    CAS  PubMed  Google Scholar 

  85. Lengronne, A. & Schwob, E. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G1 . Mol. Cell 9, 1067–1078 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Shreeram, S., Sparks, A., Lane, D. P. & Blow, J. J. Cell type-specific responses of human cells to inhibition of replication licensing. Oncogene 21, 6624–6632 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tanaka, S. & Diffley, J. F. Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation. Genes Dev. 16, 2639–2649 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Feng, D., Tu, Z., Wu, W. & Liang, C. Inhibiting the expression of DNA replication-initiation proteins induces apoptosis in human cancer cells. Cancer Res. 63, 7356–7364 (2003).

    CAS  PubMed  Google Scholar 

  89. Teer, J. K. et al. Proliferating human cells hypomorphic for origin recognition complex 2 and pre-replicative complex formation have a defect in p53 activation and Cdk2 kinase activation. J. Biol. Chem. 281, 6253–6260 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Bailis, J. M., Luche, D. D., Hunter, T. & Forsburg, S. L. Minichromosome maintenance proteins interact with checkpoint and recombination proteins to promote S-phase genome stability. Mol. Cell. Biol. 28, 1724–1738 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Burkhart, R. et al. Interactions of human nuclear proteins P1Mcm3 and P1Cdc46. Eur. J. Biochem. 228, 431–438 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Mahbubani, H. M., Chong, J. P., Chevalier, S., Thömmes, P. & Blow, J. J. Cell cycle regulation of the replication licensing system: involvement of a Cdk-dependent inhibitor. J. Cell Biol. 136, 125–135 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Edwards, M. C. et al. MCM2–7 complexes bind chromatin in a distributed pattern surrounding the origin recognition complex in Xenopus egg extracts. J. Biol. Chem. 277, 33049–33057 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Cortez, D., Glick, G. & Elledge, S. J. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc. Natl Acad. Sci. USA 101, 10078–10083 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tsao, C. C., Geisen, C. & Abraham, R. T. Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signaling. EMBO J. 23, 4660–4669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ge, X. Q., Jackson, D. A. & Blow, J. J. Dormant origins licensed by excess Mcm2–7 are required for human cells to survive replicative stress. Genes Dev. 21, 3331–3341 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Woodward, A. M. et al. Excess Mcm2–7 license dormant origins of replication that can be used under conditions of replicative stress. J. Cell Biol. 173, 673–683 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ibarra, A., Schwob, E. & Mendez, J. Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc. Natl Acad. Sci. USA 105, 8956–8961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ockey, C. H. & Saffhill, R. The comparative effects of short-term DNA inhibition on replicon synthesis in mammalian cells. Exp. Cell Res. 103, 361–373 (1976).

    Article  CAS  PubMed  Google Scholar 

  100. Taylor, J. H. Increase in DNA replication sites in cells held at the beginning of S phase. Chromosoma 62, 291–300 (1977).

    Article  CAS  PubMed  Google Scholar 

  101. Anglana, M., Apiou, F., Bensimon, A. & Debatisse, M. Dynamics of DNA replication in mammalian somatic cells: nucleotide pool modulates origin choice and interorigin spacing. Cell 114, 385–394 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Gilbert, D. M. Replication origin plasticity, Taylor-made: inhibition vs recruitment of origins under conditions of replication stress. Chromosoma 116, 341–347 (2007).

    Article  PubMed  Google Scholar 

  103. Shima, N. et al. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nature Genet. 39, 93–98 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Pruitt, S. C., Bailey, K. J. & Freeland, A. Reduced Mcm2 expression results in severe stem/progenitor cell deficiency and cancer. Stem Cells 25, 3121–3132 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Spruck, C. H., Won, K. A. & Reed, S. I. Deregulated cyclin E induces chromosome instability. Nature 401, 297–300 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Loeb, K. R. et al. A mouse model for cyclin E-dependent genetic instability and tumorigenesis. Cancer Cell 8, 35–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Lei, M. The MCM complex: its role in DNA replication and implications for cancer therapy. Curr. Cancer Drug Targets 5, 365–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Machida, Y. J., Teer, J. K. & Dutta, A. Acute reduction of an origin recognition complex (ORC) subunit in human cells reveals a requirement of ORC for Cdk2 activation. J. Biol. Chem. 280, 27624–27630 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Montagnoli, A. et al. Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells. Cancer Res. 64, 7110–7116 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Gillespie, P. J., Khoudoli, G. A., Stewart, G., Swedlow, J. R. & Blow, J. J. ELYS/MEL-28 chromatin association coordinates nuclear pore complex assembly and replication licensing. Curr. Biol. 17, 1657–1662 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tercero, J. A. & Diffley, J. F. Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412, 553–557 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are funded by Cancer Research UK grants C303/A7399 (J.J.B.) and C303/A5434 (P.J.G.).

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  1. J. Julian Blow and Peter J. Gillespie are at the Wellcome Trust Centre for Gene Regulation & Expression, University of Dundee, DD1 5EH, UK.,

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J.J.B. is a named inventor on UK Patent GB2404441: “Assay methods relating to the action of geminin in the licensing of DNA replication complexes in transformed cells.”

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DATABASES

National Cancer Institute

colorectal cancer

mammary cancer

oesophageal cancer

oral cancer

ovarian cancer

prostatic cancer

renal cancer

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Blow, J., Gillespie, P. Replication licensing and cancer — a fatal entanglement?. Nat Rev Cancer 8, 799–806 (2008). https://doi.org/10.1038/nrc2500

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