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Mutagenesis Advance Access originally published online on July 21, 2008
Mutagenesis 2008 23(5):331-339; doi:10.1093/mutage/gen039
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© The Author 2008. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Early events in the mammalian response to DNA double-strand breaks

Lucy C. Riches, Anthony M. Lynch1 and Nigel J. Gooderham*

Department of Biomolecular Medicine, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK 1Department of Genetic Toxicology, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 0DP, UK

Physical and chemical agents that induce DNA double-strand breaks (DSBs) are among the most potent mutagens. The mammalian cell response to DSB comprises a highly co-ordinated, yet complex network of proteins that have been categorized as sensors, signal transducers, mediators and effectors of damage and repair. While this provides an accessible classification system, review of the literature indicates that many proteins satisfy the criteria of more than one category, pointing towards a series of highly co-operative pathways with overlapping function. In summary, the MRE11–NBS1–RAD50 complex is necessary for achieving optimal activation of ataxia–telangiectasia-mutated (ATM) kinase, which catalyses a phosphorylation-mediated signal transduction cascade. Among the subset of proteins phosphorylated by ATM are histone H2AX (H2AX), mediator of damage checkpoint protein 1, nibrin (NBS1), P53-binding protein 1 and breast cancer protein 1, all of which subsequently redistribute into DSB-containing sub-nuclear compartments. Post-translational modification of DSB responding proteins achieves a rapid and reversible change in protein behaviour and mediates damage-specific interactions, hence imparting a high degree of vigilance to the cell. This review highlights events fundamental in maintaining genetic integrity with emphasis on early stages of the DSB response.

* To whom correspondence should be addressed. Tel: 020 7594 3188; Fax: 020 7594 3050; Email: n.gooderham{at}imperial.ac.uk

Received on February 19, 2008; revised on June 24, 2008; accepted on June 24, 2008.


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