Human Molecular Genetics Advance Access published online on September 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh316
© 2004 by Oxford University Press
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1 Institute for Cancer Studies, University of Sheffield, School of Medicine, Sheffield S10 2RX, UK
* To whom correspondence should be addressed. E-mail: m.meuth{at}sheffield.ac.uk.
Genetically distinct checkpoints, activated as a consequence of either DNA replication arrest or ionising radiation-induced DNA damage, integrate DNA repair responses into the cell cycle programme. The ATM protein kinase blocks cell cycle progression in response to DNA double strand breaks while the related ATR is important in maintaining the integrity of the DNA replication apparatus. Here we show that thymidine, which slows the progression of replication forks by depleting cellular pools of dCTP, induces a novel DNA damage response that, uniquely, depends on both ATM and ATR. Thymidine induces ATM-mediated phosphorylation of Chk2 and NBS1 and an ATM-independent phosphorylation of Chk1 and SMC1. AT cells exposed to thymidine showed decreased viability and failed to induce homologous recombination repair (HRR). Taken together, our results implicate ATM in the HRR-mediated rescue of replication forks impaired by thymidine treatment.
Article
ATM is required for the cellular response to thymidine induced replication fork stress
2 Institute for Cancer Studies, University of Sheffield, School of Medicine, Sheffield S10 2RX, UK; Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
3 Centre for Developmental Genetics, University of Sheffield, School of Medicine, Sheffield S10 2RX, UK
4 Institute for Cancer Studies, University of Sheffield, School of Medicine, Beech Hill Road, Sheffield, S10 2RX, UK
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