QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 11 July 2006
doi: 10.1242/jcs.03031

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: jcs.03031v1 119/15/3128    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tatsumi, Y. Articles by Fujita, M. Search for Related Content PubMed PubMed Citation Articles by Tatsumi, Y. Articles by Fujita, M.

Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability

Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuohku, Tokyo 104-0045, Japan

^* Author for correspondence (e-mail: mafujita{at}gan2.res.ncc.go.jp)

Accepted 3 May 2006

The activity of human Cdt1 is negatively regulated by multiple mechanisms. This suggests that Cdt1 deregulation may have a deleterious effect. Indeed, it has been suggested that overexpression of Cdt1 can induce rereplication in cancer cells and that rereplication activates Ataxia-telangiectasia-mutated (ATM) kinase and/or ATM- and Rad3-related (ATR) kinase-dependent checkpoint pathways. In this report, we highlight a new and interesting aspect of Cdt1 deregulation: data from several different systems all strongly indicate that unregulated Cdt1 overexpression at pathophysiological levels can induce chromosomal damage other than rereplication in non-transformed cells. The most important finding in these studies is that deregulated Cdt1 induces chromosomal damage and activation of the ATM-Chk2 DNA damage checkpoint pathway even in quiescent cells. These Cdt1 activities are negatively regulated by cyclin A/Cdks, probably through modification by phosphorylation. Furthermore, we found that deregulated Cdt1 induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this would be a new molecular mechanism leading to carcinogenesis.

Key words: Cdt1, Checkpoint, Chromosomal damage, Chromosomal instability

This article has been cited by other articles:

				E. M. N. Dohmann, M. P. Levesque, L. De Veylder, I. Reichardt, G. Jurgens, M. Schmid, and C. Schwechheimer The Arabidopsis COP9 signalosome is essential for G2 phase progression and genomic stability Development, June 1, 2008; 135(11): 2013 - 2022. [Abstract] [Full Text] [PDF]

				N. Sugimoto, I. Kitabayashi, S. Osano, Y. Tatsumi, T. Yugawa, M. Narisawa-Saito, A. Matsukage, T. Kiyono, and M. Fujita Identification of Novel Human Cdt1-binding Proteins by a Proteomics Approach: Proteolytic Regulation by APC/CCdh1 Mol. Biol. Cell, March 1, 2008; 19(3): 1007 - 1021. [Abstract] [Full Text] [PDF]

				E. Lau, T. Tsuji, L. Guo, S.-H. Lu, and W. Jiang The role of pre-replicative complex (pre-RC) components in oncogenesis FASEB J, December 1, 2007; 21(14): 3786 - 3794. [Abstract] [Full Text] [PDF]

				E. Liu, A. Y.-L. Lee, T. Chiba, E. Olson, P. Sun, and X. Wu The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted J. Cell Biol., November 19, 2007; 179(4): 643 - 657. [Abstract] [Full Text] [PDF]

				S. Iwahori, N. Shirata, Y. Kawaguchi, S. K. Weller, Y. Sato, A. Kudoh, S. Nakayama, H. Isomura, and T. Tsurumi Enhanced Phosphorylation of Transcription Factor Sp1 in Response to Herpes Simplex Virus Type 1 Infection Is Dependent on the Ataxia Telangiectasia-Mutated Protein J. Virol., September 15, 2007; 81(18): 9653 - 9664. [Abstract] [Full Text] [PDF]