title: ATM prevents DSB formation by coordinating SSB repair and cell cycle progression.
abstract: DNA single-strand breaks (SSBs) arise as a consequence of spontaneous DNA instability and are also formed as DNA repair intermediates. Their repair is critical because they otherwise terminate gene transcription and generate toxic DNA double-strand breaks (DSBs) on replication. To prevent the formation of DSBs, SSB repair must be completed before DNA replication. To accomplish this, cells should be able to detect unrepaired SSBs, and then delay cell cycle progression to allow more time for repair; however, to date there is no evidence supporting the coordination of SSB repair and replication in human cells. Here we report that ataxia-telangiectasia mutated kinase (ATM) plays a major role in restricting the replication of SSB-containing DNA and thus prevents DSB formation. We show that ATM is activated by SSBs and coordinates their repair with DNA replication. SSB-mediated ATM activation is followed by a G1 cell cycle delay that allows more time for repair and thus prevents the replication of damaged DNA and DSB accrual. These findings establish an unanticipated role for ATM in the signaling of DNA SSBs and provide important insight into the molecular defects leading to genetic instability in patients with ataxia-telangiectasia.
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom; and Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Khoronenkova
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom; and grigory.dianov@oncology.ox.ac.uk.
authors.forename: Grigory L
authors.initials: GL
authors.lastname: Dianov
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D020552:Comet Assay; D004247:DNA / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D016678:Genome; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D000076105:X-ray Repair Cross Complementing Protein 1; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM activation; DNA damage; DNA repair; DNA single-strand breaks; genome stability