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Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance

Brown, Eric J. and Baltimore, David (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes and Development, 17 (5). pp. 615-628. ISSN 0890-9369. PMCID PMC196009. doi:10.1101/gad.1067403.

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A Cre/lox-conditional mouse line was generated to evaluate the role of ATR in checkpoint responses to ionizing radiation (IR) and stalled DNA replication. We demonstrate that after IR treatment, ATR and ATM each contribute to early delay in M-phase entry but that ATR regulates a majority of the late phase (2–9 h post-IR). Double deletion of ATR and ATM eliminates nearly all IR-induced delay, indicating that ATR and ATM cooperate in the IR-induced G2/M-phase checkpoint. In contrast to the IR-induced checkpoint, checkpoint delay in response to stalled DNA replication is intact in ATR knockout cells and ATR/ATM andATR/p53 double-knockout cells. The DNA replication checkpoint remains intact in ATR knockout cells even though the checkpoint-stimulated inhibitory phosphorylation of Cdc2 on T14/Y15 and activating phosphorylation of the Chk1 kinase no longer occur. Thus, incomplete DNA replication in mammalian cells can prevent M-phase entry independently of ATR and inhibitory phosphorylation of Cdc2. When DNA replication inhibitors are removed, ATR knockout cells proceed to mitosis but do so with chromosome breaks, indicating that ATR provides a key genome maintenance function in S phase.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2003 by Cold Spring Harbor Laboratory Press. Received December 13, 2002;revised version accepted January 16, 2003. We especially thank Carlos Lois for assistance and training in lentivirus preparation, Shirley Pease for blastocyst injections, and Karlene Cimprich for critically reading the manuscript. We are also indebted to John Petrini, Steve Elledge, Chris Canman, and Joel Pomerantz for helpful advice; to Paul Nghiem and Thomas Glover for sharing unpublished results; and to Lilia Anonuevo, Shannon Witherow, and Bruce Kennedy for assistance in mouse care. Finally, we thank Steve Elledge, Francis Stewart, Didier Trono, Dan Van Antwerp, and Joshy Jacob for generously providing reagents. Funds for this research were provided by a grant from the NIH (2R01CA51462-14). E.J.B. was supported by a Breast Cancer Research Program postdoctoral fellowship. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact.
Funding AgencyGrant Number
Breast Cancer Research FoundationUNSPECIFIED
Subject Keywords:ATR; ATM; checkpoints; Chk1; Cdc2; chromosome breaks
Issue or Number:5
PubMed Central ID:PMC196009
Record Number:CaltechAUTHORS:20200506-070705550
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103011
Deposited By: Tony Diaz
Deposited On:06 May 2020 16:13
Last Modified:16 Nov 2021 18:17

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