Human Molecular Genetics Advance Access originally published online on September 30, 2004
Human Molecular Genetics 2004 13(23):2937-2945; doi:10.1093/hmg/ddh316
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Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved
ATM is required for the cellular response to thymidine induced replication fork stress
1Institute for Cancer Studies and 2Centre for Developmental Genetics, School of Medicine, University of Sheffield, Sheffield S10 2RX, UK
Received July 5, 2004; Revised August 13, 2004; Accepted September 24, 2004
Genetically distinct checkpoints, activated as a consequence of either DNA replication arrest or ionizing radiation-induced DNA damage, integrate DNA repair responses into the cell cycle programme. The ataxia-telangiectasia mutated (ATM) protein kinase blocks cell cycle progression in response to DNA double strand breaks, whereas 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.
* To whom correspondence should be addressed at: Institute for Cancer Studies, School of Medicine, The University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK. Tel: +44 1142713288; Fax: +44 11427195320; Email: m.meuth{at}sheffield.ac.uk
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