Canela, Andres, Marman, Yaakov, Huang, Shar-yin N, Wutz, Gordana, Tang, Wen, Zagnol-iVieira, Guido, Callen, Elsa, Wong, Nancy, Day, Amanda, Peters, Jan-Michael, Pommier, Yves, Caldecott, Keith W and Nussenzweig, André (2019) Topoisomerase II-Induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity. Molecular Cell. ISSN 1097-2765

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Abstract

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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups:	Genome Damage and Stability Centre
Related URLs:	https://www.sciencedirect.com/science/ar...
Depositing User:	Paula Amiet-West
Date Deposited:	22 Jul 2019 14:19
Last Modified:	23 Jul 2019 10:45
URI:	http://sro.sussex.ac.uk/id/eprint/84987

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