title: DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions.
abstract: A taxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA double-strand break (DSB) response. We recently showed that transcription-blocking topoisomerase I cleavage complexes (TOP1cc) produce DSBs related to R-loop formation and activate ATM in post-mitotic neurons and lymphocytes. Here we discuss how TOP1cc can produce transcription arrest with R-loop formation and generate DSBs that activate ATM, as well as data suggesting that those transcription-dependent DSBs tend to form at the IgH locus and at specific genomic sites. We also address the potential roles of ATM in response to transcription-blocking TOP1cc.
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sordet
authors.forename: Asako J
authors.initials: AJ
authors.lastname: Nakamura
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053903:DNA Breaks, Double-Stranded; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D007143:Immunoglobulin Heavy Chains; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004264:DNA Topoisomerases, Type I