Loss of Geminin Induces Rereplication in the Presence of Functional P53

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2004 May 26

PMID 15159417

Citations 131

Authors

Marina Melixetian

Andrea Ballabeni

Laura Masiero

Patrizia Gasparini

Raffaella Zamponi

Jiri Bartek

Jiri Lukas

Kristian Helin

Affiliations

Soon will be listed here.

Abstract

Strict regulation of DNA replication is essential to ensure proper duplication and segregation of chromosomes during the cell cycle, as its deregulation can lead to genomic instability and cancer. Thus, eukaryotic organisms have evolved multiple mechanisms to restrict DNA replication to once per cell cycle. Here, we show that inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle. We found a CHK1-dependent checkpoint to be activated in rereplicating cells accompanied by formation of gammaH2AX and RAD51 nuclear foci. Abrogation of the checkpoint leads to abortive mitosis and death of rereplicated cells. In addition, we demonstrate that the induction of rereplication is dependent on the replication initiation factors CDT1 and CDC6, and independent of the functional status of p53. These data show that Geminin is required for maintaining genomic stability in human cells.

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References

Abdurashidova G, Deganuto M, Klima R, Riva S, Biamonti G, Giacca M . Start sites of bidirectional DNA synthesis at the human lamin B2 origin. Science. 2000; 287(5460):2023-6. DOI: 10.1126/science.287.5460.2023. View

Madine M, Laskey R . Geminin bans replication licence. Nat Cell Biol. 2001; 3(2):E49-50. DOI: 10.1038/35055158. View

Takai H, Tominaga K, Motoyama N, Minamishima Y, Nagahama H, Tsukiyama T . Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice. Genes Dev. 2000; 14(12):1439-47. PMC: 316691. View

Liu Q, Guntuku S, Cui X, Matsuoka S, Cortez D, Tamai K . Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000; 14(12):1448-59. PMC: 316686. View

Kelly T, Brown G . Regulation of chromosome replication. Annu Rev Biochem. 2000; 69:829-80. DOI: 10.1146/annurev.biochem.69.1.829. View

Yamaguchi R, Dutta A . Proteasome inhibitors alter the orderly progression of DNA synthesis during S-phase in HeLa cells and lead to rereplication of DNA. Exp Cell Res. 2000; 261(1):271-83. DOI: 10.1006/excr.2000.5053. View

Zhou B, Elledge S . The DNA damage response: putting checkpoints in perspective. Nature. 2000; 408(6811):433-9. DOI: 10.1038/35044005. View

Wohlschlegel J, Dwyer B, Dhar S, Cvetic C, Walter J, Dutta A . Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science. 2000; 290(5500):2309-12. DOI: 10.1126/science.290.5500.2309. View

Tada S, Li A, Maiorano D, Mechali M, J Blow J . Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin. Nat Cell Biol. 2001; 3(2):107-13. PMC: 3605706. DOI: 10.1038/35055000. View

10.

Xu B, Kim St , Kastan M . Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol. 2001; 21(10):3445-50. PMC: 100266. DOI: 10.1128/MCB.21.10.3445-3450.2001. View

11.

Kuzminov A . Single-strand interruptions in replicating chromosomes cause double-strand breaks. Proc Natl Acad Sci U S A. 2001; 98(15):8241-6. PMC: 37427. DOI: 10.1073/pnas.131009198. View

12.

Feijoo C, Wu R, Jenkins D, Leitch J, Gilbert D, Smythe C . Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J Cell Biol. 2001; 154(5):913-23. PMC: 1255922. DOI: 10.1083/jcb.200104099. View

13.

Quinn L, Herr A, McGarry T, Richardson H . The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis. Genes Dev. 2001; 15(20):2741-54. PMC: 312803. DOI: 10.1101/gad.916201. View

14.

Bartek J, Lukas J . Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol. 2001; 13(6):738-47. DOI: 10.1016/s0955-0674(00)00280-5. View

15.

Arentson E, Faloon P, Seo J, Moon E, Studts J, Fremont D . Oncogenic potential of the DNA replication licensing protein CDT1. Oncogene. 2002; 21(8):1150-8. DOI: 10.1038/sj.onc.1205175. View

16.

Mihaylov I, Kondo T, Jones L, Ryzhikov S, Tanaka J, Zheng J . Control of DNA replication and chromosome ploidy by geminin and cyclin A. Mol Cell Biol. 2002; 22(6):1868-80. PMC: 135598. DOI: 10.1128/MCB.22.6.1868-1880.2002. View

17.

Roninson I, Broude E, Chang B . If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat. 2002; 4(5):303-13. DOI: 10.1054/drup.2001.0213. View

18.

Bell S, Dutta A . DNA replication in eukaryotic cells. Annu Rev Biochem. 2002; 71:333-74. DOI: 10.1146/annurev.biochem.71.110601.135425. View

19.

Coverley D, Laman H, Laskey R . Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat Cell Biol. 2002; 4(7):523-8. DOI: 10.1038/ncb813. View

20.

McGarry T . Geminin deficiency causes a Chk1-dependent G2 arrest in Xenopus. Mol Biol Cell. 2002; 13(10):3662-71. PMC: 129973. DOI: 10.1091/mbc.e02-04-0199. View