Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity

0508180 - ÚMG 2020 RIV US eng J - Článek v odborném periodiku
Canela, A. - Maman, Y. - Huang, S. N. - Wutz, G. - Tang, W. - Zagnoli-Vieira, G. - Callen, E. - Wong, N. - Day, A. - Peters, J.-M. - Caldecott, Keith - Pommier, Y. - Nussenzweig, A. P.
Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity.
Molecular Cell. Roč. 75, č. 2 (2019), s. 252-266. ISSN 1097-2765. E-ISSN 1097-4164
Institucionální podpora: RVO:68378050
Klíčová slova: 5'-tyrosyl dna phosphodiesterase * therapy-related leukemia * double-stranded breaks * genome-wide * mammalian genomes * repair * cells * pathway * cohesin * alpha
Obor OECD: Cell biology
Impakt faktor: 15.584, rok: 2019
Způsob publikování: Omezený přístup
https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30322-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276519303223%3Fshowall%3Dtrue

Topoisomerase II (TOP2) relieves torsional stress by forming transient cleavage complex intermediates (TOP2ccs) that contain TOP2-linked DNA breaks (DSBs). While TOP2ccs are normally reversible, they can be ´trapped´ by chemotherapeutic drugs such as etoposide and subsequently converted into irreversible TOP2-linked DSBs. Here, we have quantified etoposide-induced trapping of TOP2ccs, their conversion into irreversible TOP2-linked DSBs, and their processing during DNA repair genome-wide, as a function of time. We find that while TOP2 chromatin localization and trapping is independent of transcription, it requires pre-existing binding of cohesin to DNA. In contrast, the conversion of trapped TOP2ccs to irreversible DSBs during DNA repair is accelerated 2-fold at transcribed loci relative to non-transcribed loci. This conversion is dependent on proteasomal degradation and TDP2 phosphodiesterase activity. Quantitative modeling shows that only two features of pre-existing chromatin structure-namely, cohesin binding and transcriptional activity-can be used to predict the kinetics of TOP2-induced DSBs.
Trvalý link: http://hdl.handle.net/11104/0306738