title: Early events in the mammalian response to DNA double-strand breaks.
abstract: 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.
authors.affiliation: Department of Biomolecular Medicine, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Riches
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Lynch
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Gooderham
mesh_terms: D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000378:metabolism; D010748:Phosphopeptides; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D016615:Telomere / Q000201:enzymology; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D010748:Phosphopeptides; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes