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Published online
doi:10.1083/jcb.200704138
The Journal of Cell Biology, Vol. 179, No. 4, 643-657
The Rockefeller University Press, 0021-9525 $30.00
© Liu et al.
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Article

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



Enbo Liu1, Alan Yueh-Luen Lee1, Takuya Chiba1, Erin Olson1, Peiqing Sun2, and Xiaohua Wu1

1 Department of Molecular Experimental Medicine and 2 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037

Correspondence to X. Wu: xiaohwu{at}scripps.edu

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.

E. Liu and A.Y-L. Lee contributed equally to this paper.

E. Liu's present address is Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037.

T. Chiba's present address is Dept. of Investigative Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; ATRIP, ATR-interacting protein; DSB, double-stranded break; KD, kinase dead; MCM, minichromosome maintenance; pre-RC, prereplication complex; Rb, retinoblastoma protein; RPA, replication protein A; shRNA, short hairpin RNA; ssDNA, single-stranded DNA.


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