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

作者：Sordet Olivier; Redon Christophe E; Guirouilh Barbat Josee; Smith Susan; Solier Stephanie; Douarre Celine; Conti Chiara; Nakamura Asako J; Das Benu B; Nicolas Estelle; Kohn Kurt W; Bonner William M; Pommier Yves^*

来源：EMBO Reports, 2009, 10(8): 887-893.

DOI：10.1038/embor.2009.97

• ATM
• DNA double-strand break
• R-loop
• topoisomerase
• transcription

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.

• 出版日期2009-8