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First published online April 1, 2009
doi: 10.1242/10.1242/jcs.041889

Journal of Cell Science 122, 1184-1191 (2009)
Published by The Company of Biologists 2009
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Research Article

Redundant and differential regulation of multiple licensing factors ensures prevention of re-replication in normal human cells

Nozomi Sugimoto1,2, Kazumasa Yoshida1, Yasutoshi Tatsumi1,3, Takashi Yugawa1, Mako Narisawa-Saito1, Shou Waga2, Tohru Kiyono1 and Masatoshi Fujita1,*

1 Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuohku, Tokyo 104-0045, Japan
2 Faculty of Science, Japan Women's University, 2-8-1 Mejirodai, Bunkyouku, Tokyo 112-8679, Japan
3 Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuohku, Chiba 260-8717, Japan

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

Accepted 18 December 2008

When human cells enter S-phase, overlapping differential inhibitory mechanisms downregulate the replication licensing factors ORC1, CDC6 and Cdt1. Such regulation prevents re-replication so that deregulation of any individual factor alone would not be expected to induce overt re-replication. However, this has been challenged by the fact that overexpression of Cdt1 or Cdt1+CDC6 causes re-replication in some cancer cell lines. We thought it important to analyze licensing regulations in human non-cancerous cells that are resistant to Cdt1-induced re-replication and examined whether simultaneous deregulation of these licensing factors induces re-replication in two such cell lines, including human fibroblasts immortalized by telomerase. Individual overexpression of either Cdt1, ORC1 or CDC6 induced no detectable re-replication. However, with Cdt1+ORC1 or Cdt1+CDC6, some re-replication was detectable and coexpression of Cdt1+ORC1+CDC6 synergistically acted to give strong re-replication with increased mini-chromosome maintenance (MCM) loading. Coexpression of ORC1+CDC6 was without effect. These results suggest that, although Cdt1 regulation is the key step, differential regulation of multiple licensing factors ensures prevention of re-replication in normal human cells. Our findings also show for the first time the importance of ORC1 regulation for prevention of re-replication.

Key words: Cdt1, ORC1, CDC6, DNA replication, Re-replication


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