The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted

Enbo Liu, Alan Yueh Luen Lee, Takuya Chiba, Erin Olson, Peiqing Sun, Xiaohua Wu

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

DNA replication in eukaryotic cells is tightly controlled by a licensing mechanism, ensuring that each origin fires once and only once per cell cycle. We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)-mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. Thus, disruption of licensing control will not induce significant rereplication in mammalian cells when the ATR checkpoint is intact. We also demonstrate that single-stranded DNA (ssDNA) is the initial signal that activates the checkpoint when licensing control is compromised in mammalian cells. We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. Furthermore, we show that replication protein A 2 and retinoblastoma protein are both downstream targets for ATR that are important for the inhibition of DNA rereplication. We reveal the molecular mechanisms by which the ATR-mediated S phase checkpoint pathway prevents DNA rereplication and thus significantly improve our understanding of how rereplication is prevented in mammalian cells.

Original languageEnglish
Pages (from-to)643-657
Number of pages15
JournalJournal of Cell Biology
Volume179
Issue number4
DOIs
Publication statusPublished - 2007 Nov 19
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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