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. 2010 Feb 23;1(3):227–236. doi: 10.1007/s13238-010-0032-z

DNA replication licensing control and rereplication prevention

Chonghua Li 1, Jianping Jin 1,2,✉
PMCID: PMC4875085  PMID: 21203969

Abstract

Eukaryotic DNA replication is tightly restricted to only once per cell cycle in order to maintain genome stability. Cells use multiple mechanisms to control the assembly of the prereplication complex (pre-RC), a process known as replication licensing. This review focuses on the regulation of replication licensing by posttranslational modifications of the licensing factors, including phosphorylation, ubiquitylation and acetylation. These modifications are critical in establishing the pre-RC complexes as well as preventing rereplication in each cell cycle. The relationship between rereplication and diseases, including cancer and virus infection, is discussed as well.

Keywords: DNA replication licensing, rereplication, protein modification

References

  1. Abbas T., Sivaprasad U., Terai K., Amador V., Pagano M., Dutta A. PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev. 2008;22:2496–2506. doi: 10.1101/gad.1676108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aggarwal P., Lessie M.D., Lin D.I., Pontano L., Gladden A.B., Nuskey B., Goradia A., Wasik M.A., Klein-Szanto A.J., Rustgi A. K. Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev. 2007;21:2908–2922. doi: 10.1101/gad.1586007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Amador V., Ge S., Santamaria P.G., Guardavaccaro D., Pagano M. APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase. Mol Cell. 2007;27:462–473. doi: 10.1016/j.molcel.2007.06.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Andrisani O.M., Barnabas S. The transcriptional function of the hepatitis B virus X protein and its role in hepatocarcinogenesis. Int J Oncol. 1999;15:373–379. doi: 10.3892/ijo.15.2.373. [DOI] [PubMed] [Google Scholar]
  5. Arentson E., Faloon P., Seo J., Moon E., Studts J.M., Fremont D. H., Choi K. Oncogenic potential of the DNA replication licensing protein CDT1. Oncogene. 2002;21:1150–1158. doi: 10.1038/sj.onc.1205175. [DOI] [PubMed] [Google Scholar]
  6. 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. 2005;19:114–126. doi: 10.1101/gad.1255805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Arias E.E., Walter J.C. PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication. Nat Cell Biol. 2006;8:84–90. doi: 10.1038/ncb1346. [DOI] [PubMed] [Google Scholar]
  8. Arias E.E., Walter J.C. Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. Genes Dev. 2007;21:497–518. doi: 10.1101/gad.1508907. [DOI] [PubMed] [Google Scholar]
  9. Ballabeni A., Melixetian M., Zamponi R., Masiero L., Marinoni F., Helin K. Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis. EMBO J. 2004;23:3122–3132. doi: 10.1038/sj.emboj.7600314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bartkova J., Rezaei N., Liontos M., Karakaidos P., Kletsas D., Issaeva N., Vassiliou L.V., Kolettas E., Niforou K., Zoumpourlis V.C. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–637. doi: 10.1038/nature05268. [DOI] [PubMed] [Google Scholar]
  11. Beasley R.P., Hwang L.Y., Lin C.C., Chien C.S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan. Lancet. 1981;2:1129–1133. doi: 10.1016/s0140-6736(81)90585-7. [DOI] [PubMed] [Google Scholar]
  12. Bell S.P., Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem. 2002;71:333–374. doi: 10.1146/annurev.biochem.71.110601.135425. [DOI] [PubMed] [Google Scholar]
  13. Biswas N., Sanchez V., Spector D.H. Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication. J Virol. 2003;77:2369–2376. doi: 10.1128/JVI.77.4.2369-2376.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bontron S., Lin-Marq N., Strubin M. Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2. J Biol Chem. 2002;277:38847–38854. doi: 10.1074/jbc.M205722200. [DOI] [PubMed] [Google Scholar]
  15. Borlado L.R., Mendez J. CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. Carcinogenesis. 2008;29:237–243. doi: 10.1093/carcin/bgm268. [DOI] [PubMed] [Google Scholar]
  16. Bornstein G., Bloom J., Sitry-Shevah D., Nakayama K., Pagano M., Hershko A. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem. 2003;278:25752–25757. doi: 10.1074/jbc.M301774200. [DOI] [PubMed] [Google Scholar]
  17. Bouchard M.J., Schneider R.J. The enigmatic X gene of hepatitis B virus. J Virol. 2004;78:12725–12734. doi: 10.1128/JVI.78.23.12725-12734.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Bresnahan W.A., Boldogh I., Thompson E.A., Albrecht T. Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1. Virology. 1996;224:150–160. doi: 10.1006/viro.1996.0516. [DOI] [PubMed] [Google Scholar]
  19. Burke T.W., Cook J.G., Asano M., Nevins J.R. Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1. J Biol Chem. 2001;276:15397–15408. doi: 10.1074/jbc.M011556200. [DOI] [PubMed] [Google Scholar]
  20. Chen X., Barton L.F., Chi Y., Clurman B.E., Roberts J.M. Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome. Mol Cell. 2007;26:843–852. doi: 10.1016/j.molcel.2007.05.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Chuang L.C., Teixeira L.K., Wohlschlegel J.A., Henze M., Yates J. R., Mendez J., Reed S.I. Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry. Mol Cell. 2009;35:206–216. doi: 10.1016/j.molcel.2009.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Delmolino L.M., Saha P., Dutta A. Multiple mechanisms regulate subcellular localization of human CDC6. J Biol Chem. 2001;276:26947–26954. doi: 10.1074/jbc.M101870200. [DOI] [PubMed] [Google Scholar]
  23. DePamphilis M.L. Cell cycle dependent regulation of the origin recognition complex. Cell Cycle. 2005;4:70–79. doi: 10.4161/cc.4.1.1333. [DOI] [PubMed] [Google Scholar]
  24. DePamphilis M.L., Blow J.J., Ghosh S., Saha T., Noguchi K., Vassilev A. Regulating the licensing of DNA replication origins in metazoa. Curr Opin Cell Biol. 2006;18:231–239. doi: 10.1016/j.ceb.2006.04.001. [DOI] [PubMed] [Google Scholar]
  25. Di Micco R., Fumagalli M., Cicalese A., Piccinin S., Gasparini P., Luise C., Schurra C., Garre M., Nuciforo P.G., Bensimon A. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444:638–642. doi: 10.1038/nature05327. [DOI] [PubMed] [Google Scholar]
  26. Dittmer D., Mocarski E.S. Human cytomegalovirus infection inhibits G1/S transition. J Virol. 1997;71:1629–1634. doi: 10.1128/jvi.71.2.1629-1634.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Drury L.S., Perkins G., Diffley J.F. The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast. EMBO J. 1997;16:5966–5976. doi: 10.1093/emboj/16.19.5966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Elsasser S., Chi Y., Yang P., Campbell J.L. Phosphorylation controls timing of Cdc6p destruction: A biochemical analysis. Mol Biol Cell. 1999;10:3263–3277. doi: 10.1091/mbc.10.10.3263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Friedrich T.D., Bedner E., Darzynkiewicz Z., Lehman J.M. Distinct patterns of MCM protein binding in nuclei of S phase and rereplicating SV40-infected monkey kidney cells. Cytometry A. 2005;68:10–18. doi: 10.1002/cyto.a.20185. [DOI] [PubMed] [Google Scholar]
  30. Friedrich T.D., Laffin J., Lehman J.M. Simian virus 40 large T-antigen function is required for induction of tetraploid DNA content during lytic infection. J Virol. 1992;66:4576–4579. doi: 10.1128/jvi.66.7.4576-4579.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Friedrich T.D., Laffin J., Lehman J.M. Inductionof tetraploid DNA content by Simian virus 40 is dependent on T-antigen function in the G2 phase of the cell cycle. J Virol. 1994;68:4028–4030. doi: 10.1128/jvi.68.6.4028-4030.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Gershon D., Sachs L., Winocour E. The induction of cellular DNA synthesis by simian virus 40 in contact-inhibited and in X-irradiated cells. Proc Natl Acad Sci U S A. 1966;56:918–925. doi: 10.1073/pnas.56.3.918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Glozak M.A., Seto E. Acetylation/deacetylation modulates the stability of DNA replication licensing factor Cdt1. J Biol Chem. 2009;284:11446–11453. doi: 10.1074/jbc.M809394200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Gonzalez M.A., Tachibana K.E., Laskey R.A., Coleman N. Control of DNA replication and its potential clinical exploitation. Nat Rev Cancer. 2005;5:135–141. doi: 10.1038/nrc1548. [DOI] [PubMed] [Google Scholar]
  35. Hatanaka M., Dulbecco R. Induction of DNA synthesis by SV40. Proc Natl Acad Sci U S A. 1966;56:736–740. doi: 10.1073/pnas.56.2.736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Havens C.G., Walter J.C. Docking of a specialized PIP Box onto chromatin-bound PCNA creates a degron for the ubiquitin ligase CRL4Cdt2. Mol Cell. 2009;35:93–104. doi: 10.1016/j.molcel.2009.05.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hook S.S., Lin J.J., Dutta A. Mechanisms to control rereplication and implications for cancer. Curr Opin Cell Biol. 2007;19:663–671. doi: 10.1016/j.ceb.2007.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Hsu J.Y., Reimann J.D., Sorensen C.S., Lukas J., Jackson P. K. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1) Nat Cell Biol. 2002;4:358–366. doi: 10.1038/ncb785. [DOI] [PubMed] [Google Scholar]
  39. Hu J., McCall C.M., Ohta T., Xiong Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004;6:1003–1009. doi: 10.1038/ncb1172. [DOI] [PubMed] [Google Scholar]
  40. 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. 2006;281:3753–3756. doi: 10.1074/jbc.C500464200. [DOI] [PubMed] [Google Scholar]
  41. Jiang W., Wells N.J., Hunter T. Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6. Proc Natl Acad Sci U S A. 1999;96:6193–6198. doi: 10.1073/pnas.96.11.6193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. 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. 2006;23:709–721. doi: 10.1016/j.molcel.2006.08.010. [DOI] [PubMed] [Google Scholar]
  43. 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. 2007;17:966–972. doi: 10.1016/j.cub.2007.04.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Kim Y., Kipreos E.T. The Caenorhabditis elegans replication licensing factor CDT-1 is targeted for degradation by the CUL-4/DDB-1 complex. Mol Cell Biol. 2007;27:1394–1406. doi: 10.1128/MCB.00736-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kim J., Kipreos E.T. Control of the Cdc6 replication licensing factor in metazoa: the role of nuclear export and the CUL4 ubiquitin ligase. Cell Cycle. 2008;7:146–150. doi: 10.4161/cc.7.2.5282. [DOI] [PubMed] [Google Scholar]
  46. Kim Y., Starostina N.G., Kipreos E.T. The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev. 2008;22:2507–2519. doi: 10.1101/gad.1703708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kittelmann K., Rau P., Gronenborn B., Jeske H. Plant geminivirus rep protein induces rereplication in fission yeast. J Virol. 2009;83:6769–6778. doi: 10.1128/JVI.02491-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Labib K., Diffley J.F., Kearsey S.E. G1-phase and B-type cyclins exclude the DNA-replication factor Mcm4 from the nucleus. Nat Cell Biol. 1999;1:415–422. doi: 10.1038/15649. [DOI] [PubMed] [Google Scholar]
  49. Lewin B. Genes VII. New York: Oxford University Press; 2000. [Google Scholar]
  50. Li A., Blow J.J. Non-proteolytic inactivation of geminin requires CDK-dependent ubiquitination. Nat Cell Biol. 2004;6:260–267. doi: 10.1038/ncb1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Li C.J., Vassilev A., DePamphilis M.L. Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition complex’s largest subunit (Orc1) from binding to chromatin during mitosis. Mol Cell Biol. 2004;24:5875–5886. doi: 10.1128/MCB.24.13.5875-5886.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Li X., Amazit L., Long W., Lonard D.M., Monaco J.J., O’Malley B.W. Ubiquitin- and ATP-independent proteolytic turnover of p21 by the REGgamma-proteasome pathway. Mol Cell. 2007;26:831–842. doi: 10.1016/j.molcel.2007.05.028. [DOI] [PubMed] [Google Scholar]
  53. Li X., Zhao Q., Liao R., Sun P., Wu X. The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. J Biol Chem. 2003;278:30854–30858. doi: 10.1074/jbc.C300251200. [DOI] [PubMed] [Google Scholar]
  54. Liku M.E., Nguyen V.Q., Rosales A.W., Irie K., Li J.J. CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the MCM2-7 complex prevents chromosomal rereplication. Mol Biol Cell. 2005;16:5026–5039. doi: 10.1091/mbc.E05-05-0412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Liu E., Li X., Yan F., Zhao Q., Wu X. Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation. J Biol Chem. 2004;279:17283–17288. doi: 10.1074/jbc.C300549200. [DOI] [PubMed] [Google Scholar]
  56. Lizuka M., Matsui T., Takisawa H., Smith M.M. Regulation of replication licensing by acetyltransferase Hbo1. Mol Cell Biol. 2006;26:1098–1108. doi: 10.1128/MCB.26.3.1098-1108.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Iizuka M., Stillman B. Histone acetyltransferase HBO1 interacts with the ORC1 subunit of the human initiator protein. J Biol Chem. 1999;274:23027–23034. doi: 10.1074/jbc.274.33.23027. [DOI] [PubMed] [Google Scholar]
  58. Lovejoy C.A., Lock K., Yenamandra A., Cortez D. DDB1 maintains genome integrity through regulation of Cdt1. Mol Cell Biol. 2006;26:7977–7990. doi: 10.1128/MCB.00819-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Lu M., Shenk T. Human cytomegalovirus infection inhibits cell cycle progression at multiple points, including the transition from G1 to S. J Virol. 1996;70:8850–8857. doi: 10.1128/jvi.70.12.8850-8857.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Lutzmann M., Mechali M. MCM9 binds Cdt1 and is required for the assembly of prereplication complexes. Mol Cell. 2008;31:190–200. doi: 10.1016/j.molcel.2008.07.001. [DOI] [PubMed] [Google Scholar]
  61. Machida Y.J., Dutta A. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 2007;21:184–194. doi: 10.1101/gad.1495007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Masai H., Arai K. Cdc7 kinase complex: a key regulator in the initiation of DNA replication. J Cell Physiol. 2002;190:287–296. doi: 10.1002/jcp.10070. [DOI] [PubMed] [Google Scholar]
  63. McGarry T.J., Kirschner M.W. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998;93:1043–1053. doi: 10.1016/s0092-8674(00)81209-x. [DOI] [PubMed] [Google Scholar]
  64. Mendez J., Zou-Yang X.H., Kim S.Y., Hidaka M., Tansey W.P., Stillman B. Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol Cell. 2002;9:481–491. doi: 10.1016/s1097-2765(02)00467-7. [DOI] [PubMed] [Google Scholar]
  65. Mimura S., Seki T., Tanaka S., Diffley J.F. Phosphorylation-dependent binding of mitotic cyclins to Cdc6 contributes to DNA replication control. Nature. 2004;431:1118–1123. doi: 10.1038/nature03024. [DOI] [PubMed] [Google Scholar]
  66. Miotto B., Struhl K. HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev. 2008;22:2633–2638. doi: 10.1101/gad.1674108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Miotto B., Struhl K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by Geminin. Mol Cell. 2010;37:57–66. doi: 10.1016/j.molcel.2009.12.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Moldovan G.L., Pfander B., Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007;129:665–679. doi: 10.1016/j.cell.2007.05.003. [DOI] [PubMed] [Google Scholar]
  69. Montagnoli A., Tenca P., Sola F., Carpani D., Brotherton D., Albanese C., Santocanale C. Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells. Cancer Res. 2004;64:7110–7116. doi: 10.1158/0008-5472.CAN-04-1547. [DOI] [PubMed] [Google Scholar]
  70. Montagnoli A., Valsasina B., Croci V., Menichincheri M., Rainoldi S., Marchesi V., Tibolla M., Tenca P., Brotherton D., Albanese C. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008;4:357–365. doi: 10.1038/nchembio.90. [DOI] [PubMed] [Google Scholar]
  71. Nguyen V.Q., Co C., Irie K., Li J.J. Clb/Cdc28 kinases promote nuclear export of the replication initiator proteins MCM2-7. Curr Biol. 2000;10:195–205. doi: 10.1016/s0960-9822(00)00337-7. [DOI] [PubMed] [Google Scholar]
  72. Nguyen V.Q., Co C., Li J.J. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature. 2001;411:1068–1073. doi: 10.1038/35082600. [DOI] [PubMed] [Google Scholar]
  73. Nishitani H., Lygerou Z. Control of DNA replication licensing in a cell cycle. Genes Cells. 2002;7:523–534. doi: 10.1046/j.1365-2443.2002.00544.x. [DOI] [PubMed] [Google Scholar]
  74. Nishitani H., Shiomi Y., Iida H., Michishita M., Takami T., Tsurimoto T. CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation. J Biol Chem. 2008;283:29045–29052. doi: 10.1074/jbc.M806045200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Nishitani H., Sugimoto N., Roukos V., Nakanishi Y., Saijo M., Obuse C., Tsurimoto T., Nakayama K.I., Nakayama K., Fujita M. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J. 2006;25:1126–1136. doi: 10.1038/sj.emboj.7601002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Paolinelli R., Mendoza-Maldonado R., Cereseto A., Giacca M. Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Nat Struct Mol Biol. 2009;16:412–420. doi: 10.1038/nsmb.1583. [DOI] [PubMed] [Google Scholar]
  77. Perry M.B., Lehman J.M. Activities of SV40 T antigen necessary for the induction of tetraploid DNA content in permissive CV-1 cells. Cytometry. 1998;31:251–259. [PubMed] [Google Scholar]
  78. 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. 1999;18:396–410. doi: 10.1093/emboj/18.2.396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Pickart C.M. Back to the future with ubiquitin. Cell. 2004;116:181–190. doi: 10.1016/s0092-8674(03)01074-2. [DOI] [PubMed] [Google Scholar]
  80. Prives C., Gottifredi V. The p21 and PCNA partnership: a new twist for an old plot. Cell Cycle. 2008;7:3840–3846. doi: 10.4161/cc.7.24.7243. [DOI] [PubMed] [Google Scholar]
  81. Rakotomalala L., Studach L., Wang W.H., Gregori G., Hullinger R. L., Andrisani O. Hepatitis B virus X protein increases the Cdt1-to-geminin ratio inducing DNA re-replication and polyploidy. J Biol Chem. 2008;283:28729–28740. doi: 10.1074/jbc.M802751200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. 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. 2006;7:1134–1139. doi: 10.1038/sj.embor.7400827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Rape M., Reddy S.K., Kirschner M.W. The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell. 2006;124:89–103. doi: 10.1016/j.cell.2005.10.032. [DOI] [PubMed] [Google Scholar]
  84. Roberts S., Kingsbury S.R., Stoeber K., Knight G.L., Gallimore P. H., Williams G.H. Identification of an arginine-rich motif in human papillomavirus type 1 E1;E4 protein necessary for E4-mediated inhibition of cellular DNA synthesis in vitro and in cells. J Virol. 2008;82:9056–9064. doi: 10.1128/JVI.01080-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Saha T., Ghosh S., Vassilev A., DePamphilis M.L. Ubiquitylation, phosphorylation and Orc2 modulate the subcellular location of Orc1 and prevent it from inducing apoptosis. J Cell Sci. 2006;119:1371–1382. doi: 10.1242/jcs.02851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Sansam C.L., Shepard J.L., Lai K., Ianari A., Danielian P.S., Amsterdam A., Hopkins N., Lees J.A. DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes Dev. 2006;20:3117–3129. doi: 10.1101/gad.1482106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Senga T., Sivaprasad U., Zhu W., Park J.H., Arias E.E., Walter J. C., Dutta A. PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J Biol Chem. 2006;281:6246–6252. doi: 10.1074/jbc.M512705200. [DOI] [PubMed] [Google Scholar]
  88. Seo J., Chung Y.S., Sharma G.G., Moon E., Burack W.R., Pandita T.K., Choi K. Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53. Oncogene. 2005;24:8176–8186. doi: 10.1038/sj.onc.1208881. [DOI] [PubMed] [Google Scholar]
  89. Sugimoto N., Tatsumi Y., Tsurumi T., Matsukage A., Kiyono T., Nishitani H., Fujita M. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004;279:19691–19697. doi: 10.1074/jbc.M313175200. [DOI] [PubMed] [Google Scholar]
  90. Sugimoto N., Yoshida K., Tatsumi Y., Yugawa T., Narisawa-Saito M., Waga S., Kiyono T., Fujita M. Redundant and differential regulation of multiple licensing factors ensures prevention of re-replication in normal human cells. J Cell Sci. 2009;122:1184–1191. doi: 10.1242/jcs.041889. [DOI] [PubMed] [Google Scholar]
  91. Swords R., Mahalingam D., O’Dwyer M., Santocanale C., Kelly K., Carew J., Giles F. Cdc7 kinase- A new target for drug development. Eur J Cancer. 2010;46:33–40. doi: 10.1016/j.ejca.2009.09.020. [DOI] [PubMed] [Google Scholar]
  92. 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. Nat Cell Biol. 2001;3:107–113. doi: 10.1038/35055000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. 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. 2005;280:23416–23423. doi: 10.1074/jbc.M501208200. [DOI] [PubMed] [Google Scholar]
  94. Tran K., Mahr J.A., Choi J., Teodoro J.G., Green M.R., Spector Accumulation of substrates of the anaphasepromoting complex (APC) during human cytomegalovirus infection is associated with the phosphorylation of Cdh1 and the dissociation and relocalization of APC subunits. J Virol. 2008;82:529–537. doi: 10.1128/JVI.02010-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Vaziri C., Saxena S., Jeon Y., Lee C., Murata K., Machida Y., Wagle N., Hwang D.S., Dutta A. A p53-dependent checkpoint pathway prevents rereplication. Mol Cell. 2003;11:997–1008. doi: 10.1016/s1097-2765(03)00099-6. [DOI] [PubMed] [Google Scholar]
  96. Williams G.H., Stoeber K. Cell cycle markers in clinical oncology. Curr Opin Cell Biol. 2007;19:672–679. doi: 10.1016/j.ceb.2007.10.005. [DOI] [PubMed] [Google Scholar]
  97. Wohlschlegel J.A., Dwyer B.T., Dhar S.K., Cvetic C., Walter J.C., Dutta A. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science. 2000;290:2309–2312. doi: 10.1126/science.290.5500.2309. [DOI] [PubMed] [Google Scholar]
  98. Wu X., Avni D., Chiba T., Yan F., Zhao Q., Lin Y., Heng H., Livingston D. SV40 Tantigen interacts with Nbs1 to disrupt DNA replication control. Genes Dev. 2004;18:1305–1316. doi: 10.1101/gad.1182804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Yanow S.K., Lygerou Z., Nurse P. Expression of Cdc18/Cdc6 and Cdt1 during G2 phase induces initiation of DNA replication. EMBO J. 2001;20:4648–4656. doi: 10.1093/emboj/20.17.4648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Yu Z.K., Gervais J.L., Zhang H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21 (CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci U S A. 1998;95:11324–11329. doi: 10.1073/pnas.95.19.11324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Zhong W., Feng H., Santiago F.E., Kipreos E.T. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature. 2003;423:885–889. doi: 10.1038/nature01747. [DOI] [PubMed] [Google Scholar]
  102. Zhu W., Depamphilis M.L. Selective killing of cancer cells by suppression of geminin activity. Cancer Res. 2009;69:4870–4877. doi: 10.1158/0008-5472.CAN-08-4559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Zoulim F., Saputelli J., Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol. 1994;68:2026–2030. doi: 10.1128/jvi.68.3.2026-2030.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

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