RGD Reference Report - Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks. - Rat Genome Database

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Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks.

Authors: Sordet, O  Redon, CE  Guirouilh-Barbat, J  Smith, S  Solier, S  Douarre, C  Conti, C  Nakamura, AJ  Das, BB  Nicolas, E  Kohn, KW  Bonner, WM  Pommier, Y 
Citation: Sordet O, etal., EMBO Rep. 2009 Aug;10(8):887-93. Epub 2009 Jun 26.
RGD ID: 2316101
Pubmed: PMID:19557000   (View Abstract at PubMed)
PMCID: PMC2726680   (View Article at PubMed Central)
DOI: DOI:10.1038/embor.2009.97   (Journal Full-text)

Ataxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA damage response (DDR). As neurons have high rates of transcription that require topoisomerase I (TOP1), we investigated whether TOP1 cleavage complexes (TOP1cc)-which are potent transcription-blocking lesions-also produce transcription-dependent DNA double-strand breaks (DSBs) with ATM activation. We show the induction of DSBs and DDR activation in post-mitotic primary neurons and lymphocytes treated with camptothecin, with the induction of nuclear DDR foci containing activated ATM, gamma-H2AX (phosphorylated histone H2AX), activated CHK2 (checkpoint kinase 2), MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1). The DSB-ATM-DDR pathway was suppressed by inhibiting transcription and gamma-H2AX signals were reduced by RNase H1 transfection, which removes transcription-mediated R-loops. Thus, we propose that Top1cc produce transcription arrests with R-loop formation and generate DSBs that activate ATM in post-mitotic cells.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
DNA damage response  IMP 2316101 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)


Additional Information