Abstract:
: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.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
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 Ydoi
10.1038/embor.2009.97subject
Has Abstractpub_date
2009-08-01 00:00:00pages
887-93issue
8eissn
1469-221Xissn
1469-3178pii
embor200997journal_volume
10pub_type
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