Orateur
Dr
Olivier Sordet
(CRCT-INSERM UMR1037)
Description
Topoisomerase I (Top1) relaxes DNA supercoiling generated during transcription by producing transient Top1-DNA cleavage complexes (Top1cc). These Top1cc intermediates can be stabilized under a broad range of physiological conditions including oxidative base damage, alkylation by carcinogenic compounds and nicks, and by ribonucleotide misincorporation. Stabilized Top1cc are potent transcription-blocking lesions and our observations indicate that they can be converted into DNA double-strand breaks (1-4). We will discuss the mechanism of production of these co-transcriptional DNA double-strand breaks and their potential relevance in the pathogenesis of neurodegenerative diseases.
1. A. Cristini et al., DNA-PK triggers histone ubiquitination and signaling in response to DNA double-strand breaks produced during the repair of transcription-blocking topoisomerase I lesions. Nucleic Acids Res In press., (2015).
2. O. Sordet et al., Hyperphosphorylation of RNA polymerase II in response to topoisomerase I cleavage complexes and its association with transcription- and BRCA1-dependent degradation of topoisomerase I. J Mol Biol 381, 540-549 (2008).
3. O. Sordet, A. J. Nakamura, C. E. Redon, Y. Pommier, DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions. Cell cycle (Georgetown, Tex 9, 274-278 (2010).
4. O. Sordet et al., Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks. EMBO Rep 10, 887-893 (2009).
Auteur principal
Dr
Olivier Sordet
(CRCT-INSERM UMR1037)
