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Volume 10Nov 2009

Scientific Report

  • EMBO reports (2009) 10, 887 - 893
  • doi:10.1038/embor.2009.97

Published online: 26 June 2009

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

Olivier Sordet1,†, Christophe E Redon1, Josée Guirouilh-Barbat1, Susan Smith2, Stéphanie Solier1, Céline Douarre1, Chiara Conti1, Asako J Nakamura1, Benu B Das1, Estelle Nicolas3, Kurt W Kohn1, William M Bonner1 & Yves Pommier1

  1. Laboratory of Molecular Pharmacology, National Cancer Institute, Building 37, Room 5068, NIH, Bethesda, MD 20892-4255, USA
  2. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
  3. LBCMCP, UMR5088 CNRS, Université Paul Sabatier, 31062 Toulouse, France

Correspondence to:

Yves Pommier, Tel: +1 301 496 5944; Fax: +1 301 402 0752;
E-mail: pommier@nih.gov

†Present address: INSERM U563, Institut Claudius Regaud, 31052 Toulouse, France

Received 6 January 2009; Revised 30 March 2009; Accepted 9 April 2009

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.

  • Keywords:

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