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

Nozomi Sugimoto, Kazumasa Yoshida, Yasutoshi Tatsumi, Takashi Yugawa, Mako Narisawa-Saito, Shou Waga, Tohru Kiyono, Masatoshi Fujita

研究成果: Contribution to journalArticle査読

22 被引用数 (Scopus)

抄録

When human cells enter S-phase, overlapping differential inhibitory mechanisms downregulate the replication licensing factors ORC1, CDC6 and Cdt1. Such regulation prevents rereplication 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.

本文言語英語
ページ(範囲)1184-1191
ページ数8
ジャーナルJournal of cell science
122
8
DOI
出版ステータス出版済み - 4 15 2009

All Science Journal Classification (ASJC) codes

  • Cell Biology

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