A p53-dependent checkpoint pathway prevents rereplication

Cyrus Vaziri, Sandeep Saxena, Yesu Jeon, Charles Lee, Kazutaka Murata, Yuichi Machida, Nikhil Wagle, Deog Su Hwang, Anindya Dutta

Research output: Contribution to journalArticlepeer-review

324 Scopus citations

Abstract

Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability.

Original languageEnglish (US)
Pages (from-to)997-1008
Number of pages12
JournalMolecular Cell
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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