This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhu, W.
Right arrow Articles by Dutta, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, W.
Right arrow Articles by Dutta, A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2004, p. 7140-7150, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7140-7150.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Rereplication by Depletion of Geminin Is Seen Regardless of p53 Status and Activates a G2/M Checkpoint

Wenge Zhu, Yuefeng Chen, and Anindya Dutta*

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Received 2 March 2004/ Returned for modification 9 April 2004/ Accepted 28 May 2004

Genomic DNA replication is tightly controlled to ensure that DNA replication occurs once per cell cycle; loss of this control leads to genomic instability. Geminin, a DNA replication inhibitor, plays an important role in regulation of DNA replication. To investigate the role of human geminin in the maintenance of genomic stability, we eliminated geminin by RNA interference in human cancer cells. Depletion of geminin led to overreplication and the formation of giant nuclei in cells that had wild-type or mutant p53. We found that overreplication caused by depletion of geminin activated both Chk1 and Chk2, which then phosphorylated Cdc25C on Ser216, resulting in its sequestration outside the nucleus, thus inhibiting cyclin B-Cdc2 activity. This activated G2/M checkpoint prevented cells with overreplicated DNA from entering mitosis. Addition of caffeine, UCN-01, or inhibitors of checkpoint pathways or silencing of Chk1 suppressed the accumulation of overreplicated cells and promoted apoptosis. From these results, we conclude that geminin is required for suppressing overreplication in human cells and that a G2/M checkpoint restricts the proliferation of cells with overreplicated DNA.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908. Phone: (434) 924-1277. Fax: (434) 924-5069. E-mail: ad8q{at}virginia.edu.

Molecular and Cellular Biology, August 2004, p. 7140-7150, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7140-7150.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhu, W., DePamphilis, M. L. (2009). Selective Killing of Cancer Cells by Suppression of Geminin Activity. Cancer Res. 69: 4870-4877 [Abstract] [Full Text]  
  • Ballabeni, A., Zamponi, R., Caprara, G., Melixetian, M., Bossi, S., Masiero, L., Helin, K. (2009). Human CDT1 Associates with CDC7 and Recruits CDC45 to Chromatin during S Phase. J. Biol. Chem. 284: 3028-3036 [Abstract] [Full Text]  
  • Dorn, E. S., Chastain, P. D. II, Hall, J. R., Cook, J. G. (2009). Analysis of re-replication from deregulated origin licensing by DNA fiber spreading. Nucleic Acids Res 37: 60-69 [Abstract] [Full Text]  
  • Mehrotra, S., Maqbool, S. B., Kolpakas, A., Murnen, K., Calvi, B. R. (2008). Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress. Genes Dev. 22: 3158-3171 [Abstract] [Full Text]  
  • Ganier, O., Mechali, M. (2008). New cell or new cycle?. Genes Dev. 22: 2908-2913 [Abstract] [Full Text]  
  • Ullah, Z., Kohn, M. J., Yagi, R., Vassilev, L. T., DePamphilis, M. L. (2008). Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes Dev. 22: 3024-3036 [Abstract] [Full Text]  
  • Nishitani, H., Shiomi, Y., Iida, H., Michishita, M., Takami, T., Tsurimoto, T. (2008). 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. 283: 29045-29052 [Abstract] [Full Text]  
  • Rakotomalala, L., Studach, L., Wang, W.-H., Gregori, G., Hullinger, R. L., Andrisani, O. (2008). Hepatitis B Virus X Protein Increases the Cdt1-to-Geminin Ratio Inducing DNA Re-replication and Polyploidy. J. Biol. Chem. 283: 28729-28740 [Abstract] [Full Text]  
  • Kim, Y., Starostina, N. G., Kipreos, E. T. (2008). The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev. 22: 2507-2519 [Abstract] [Full Text]  
  • Hall, J. R., Lee, H. O., Bunker, B. D., Dorn, E. S., Rogers, G. C., Duronio, R. J., Cook, J. G. (2008). Cdt1 and Cdc6 Are Destabilized by Rereplication-induced DNA Damage. J. Biol. Chem. 283: 25356-25363 [Abstract] [Full Text]  
  • Petermann, E., Helleday, T., Caldecott, K. W. (2008). Claspin Promotes Normal Replication Fork Rates in Human Cells. Mol. Biol. Cell 19: 2373-2378 [Abstract] [Full Text]  
  • Teer, J. K., Dutta, A. (2008). Human Cdt1 Lacking the Evolutionarily Conserved Region That Interacts with MCM2-7 Is Capable of Inducing Re-replication. J. Biol. Chem. 283: 6817-6825 [Abstract] [Full Text]  
  • Liu, E., Lee, A. Y.-L., Chiba, T., Olson, E., Sun, P., Wu, X. (2007). The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted. JCB 179: 643-657 [Abstract] [Full Text]  
  • Verschuren, E. W., Ban, K. H., Masek, M. A., Lehman, N. L., Jackson, P. K. (2007). 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 [Abstract] [Full Text]  
  • Lee, A. Y.-L., Liu, E., Wu, X. (2007). The Mre11/Rad50/Nbs1 Complex Plays an Important Role in the Prevention of DNA Rereplication in Mammalian Cells. J. Biol. Chem. 282: 32243-32255 [Abstract] [Full Text]  
  • Lin, J. J., Dutta, A. (2007). ATR Pathway Is the Primary Pathway for Activating G2/M Checkpoint Induction After Re-replication. J. Biol. Chem. 282: 30357-30362 [Abstract] [Full Text]  
  • Zhu, W., Ukomadu, C., Jha, S., Senga, T., Dhar, S. K., Wohlschlegel, J. A., Nutt, L. K., Kornbluth, S., Dutta, A. (2007). Mcm10 and And-1/CTF4 recruit DNA polymerase {alpha} to chromatin for initiation of DNA replication. Genes Dev. 21: 2288-2299 [Abstract] [Full Text]  
  • Hall, J. R., Kow, E., Nevis, K. R., Lu, C. K., Luce, K. S., Zhong, Q., Cook, J. G. (2007). Cdc6 Stability Is Regulated by the Huwe1 Ubiquitin Ligase after DNA Damage. Mol. Biol. Cell 18: 3340-3350 [Abstract] [Full Text]  
  • Di Fiore, B., Pines, J. (2007). Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C. JCB 177: 425-437 [Abstract] [Full Text]  
  • Roukos, V., Iliou, M. S., Nishitani, H., Gentzel, M., Wilm, M., Taraviras, S., Lygerou, Z. (2007). Geminin Cleavage during Apoptosis by Caspase-3 Alters Its Binding Ability to the SWI/SNF Subunit Brahma. J. Biol. Chem. 282: 9346-9357 [Abstract] [Full Text]  
  • Arias, E. E., Walter, J. C. (2007). Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. Genes Dev. 21: 497-518 [Abstract] [Full Text]  
  • Machida, Y. J., Dutta, A. (2007). The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 21: 184-194 [Abstract] [Full Text]  
  • Sansam, C. L., Shepard, J. L., Lai, K., Ianari, A., Danielian, P. S., Amsterdam, A., Hopkins, N., Lees, J. A. (2006). DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes Dev. 20: 3117-3129 [Abstract] [Full Text]  
  • Lovejoy, C. A., Lock, K., Yenamandra, A., Cortez, D. (2006). DDB1 Maintains Genome Integrity through Regulation of Cdt1. Mol. Cell. Biol. 26: 7977-7990 [Abstract] [Full Text]  
  • Hara, K., Nakayama, K. I., Nakayama, K. (2006). Geminin is essential for the development of preimplantation mouse embryos. GENES CELLS 11: 1281-1293 [Abstract] [Full Text]  
  • Tatsumi, Y., Sugimoto, N., Yugawa, T., Narisawa-Saito, M., Kiyono, T., Fujita, M. (2006). Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability. J. Cell Sci. 119: 3128-3140 [Abstract] [Full Text]  
  • Gonzalez, M. A., Tachibana, K.-e K., Adams, D. J., van der Weyden, L., Hemberger, M., Coleman, N., Bradley, A., Laskey, R. A. (2006). Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development. Genes Dev. 20: 1880-1884 [Abstract] [Full Text]  
  • Zhu, W., Dutta, A. (2006). 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 [Abstract] [Full Text]  
  • Green, B. M., Morreale, R. J., Ozaydin, B., DeRisi, J. L., Li, J. J. (2006). Genome-wide Mapping of DNA Synthesis in Saccharomyces cerevisiae Reveals That Mechanisms Preventing Reinitiation of DNA Replication Are Not Redundant. Mol. Biol. Cell 17: 2401-2414 [Abstract] [Full Text]  
  • Tanny, R. E., MacAlpine, D. M., Blitzblau, H. G., Bell, S. P. (2006). Genome-wide Analysis of Re-replication Reveals Inhibitory Controls That Target Multiple Stages of Replication Initiation. Mol. Biol. Cell 17: 2415-2423 [Abstract] [Full Text]  
  • Petermann, E., Maya-Mendoza, A., Zachos, G., Gillespie, D. A. F., Jackson, D. A., Caldecott, K. W. (2006). Chk1 Requirement for High Global Rates of Replication Fork Progression during Normal Vertebrate S Phase. Mol. Cell. Biol. 26: 3319-3326 [Abstract] [Full Text]  
  • Senga, T., Sivaprasad, U., Zhu, W., Park, J. H., Arias, E. E., Walter, J. C., Dutta, A. (2006). PCNA Is a Cofactor for Cdt1 Degradation by CUL4/DDB1-mediated N-terminal Ubiquitination. J. Biol. Chem. 281: 6246-6252 [Abstract] [Full Text]  
  • Iizuka, M., Matsui, T., Takisawa, H., Smith, M. M. (2006). Regulation of Replication Licensing by Acetyltransferase Hbo1. Mol. Cell. Biol. 26: 1098-1108 [Abstract] [Full Text]  
  • Ryu, S., Holzschuh, J., Erhardt, S., Ettl, A.-K., Driever, W. (2005). Depletion of minichromosome maintenance protein 5 in the zebrafish retina causes cell-cycle defect and apoptosis. Proc. Natl. Acad. Sci. USA 102: 18467-18472 [Abstract] [Full Text]  
  • Remus, D., Blanchette, M., Rio, D. C., Botchan, M. R. (2005). CDK Phosphorylation Inhibits the DNA-binding and ATP-hydrolysis Activities of the Drosophila Origin Recognition Complex. J. Biol. Chem. 280: 39740-39751 [Abstract] [Full Text]  
  • Liku, M. E., Nguyen, V. Q., Rosales, A. W., Irie, K., Li, J. J. (2005). CDK Phosphorylation of a Novel NLS-NES Module Distributed between Two Subunits of the Mcm2-7 Complex Prevents Chromosomal Rereplication. Mol. Biol. Cell 16: 5026-5039 [Abstract] [Full Text]  
  • May, N. R., Thomer, M., Murnen, K. F., Calvi, B. R. (2005). Levels of the origin-binding protein Double parked and its inhibitor Geminin increase in response to replication stress. J. Cell Sci. 118: 4207-4217 [Abstract] [Full Text]  
  • Archambault, V., Ikui, A. E., Drapkin, B. J., Cross, F. R. (2005). Disruption of Mechanisms That Prevent Rereplication Triggers a DNA Damage Response. Mol. Cell. Biol. 25: 6707-6721 [Abstract] [Full Text]  
  • Seo, S., Herr, A., Lim, J.-W., Richardson, G. A., Richardson, H., Kroll, K. L. (2005). Geminin regulates neuronal differentiation by antagonizing Brg1 activity. Genes Dev. 19: 1723-1734 [Abstract] [Full Text]  
  • Takeda, D. Y., Parvin, J. D., Dutta, A. (2005). 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 [Abstract] [Full Text]  
  • Yanagi, K.-i., Mizuno, T., Tsuyama, T., Tada, S., Iida, Y., Sugimoto, A., Eki, T., Enomoto, T., Hanaoka, F. (2005). Caenorhabditis elegans Geminin Homologue Participates in Cell Cycle Regulation and Germ Line Development. J. Biol. Chem. 280: 19689-19694 [Abstract] [Full Text]  
  • Dutta, A. (2005). Anticancer Therapy against Initiation of DNA Replication. aacredbook 2005: 243-245 [Full Text]  
  • Machida, Y. J., Dutta, A. (2005). Cellular Checkpoint Mechanisms Monitoring Proper Initiation of DNA Replication. J. Biol. Chem. 280: 6253-6256 [Full Text]  
  • Tsuyama, T., Tada, S., Watanabe, S., Seki, M., Enomoto, T. (2005). Licensing for DNA replication requires a strict sequential assembly of Cdc6 and Cdt1 onto chromatin in Xenopus egg extracts. Nucleic Acids Res 33: 765-775 [Abstract] [Full Text]  
  • Ferenbach, A., Li, A., Brito-Martins, M., Blow, J. J. (2005). Functional domains of the Xenopus replication licensing factor Cdt1. Nucleic Acids Res 33: 316-324 [Abstract] [Full Text]  
  • Yoshida, K., Takisawa, H., Kubota, Y. (2005). Intrinsic nuclear import activity of geminin is essential to prevent re-initiation of DNA replication in Xenopus eggs. GENES CELLS 10: 63-73 [Abstract] [Full Text]  
  • Arias, E. E., Walter, J. C. (2005). Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. Genes Dev. 19: 114-126 [Abstract] [Full Text]  
  • Green, B. M., Li, J. J. (2005). Loss of Rereplication Control in Saccharomyces cerevisiae Results in Extensive DNA Damage. Mol. Biol. Cell 16: 421-432 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»