MOLECULAR-CELL-D-18-02097.pdf (17.36 MB)
Topoisomerase II-Induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity
journal contribution
posted on 2023-06-07, 06:39 authored by Andres Canela, Yaakov Marman, Shar-yin N Huang, Gordana Wutz, Wen Tang, Guido Zagnol-iVieira, Elsa Callen, Nancy Wong, Amanda Day, Jan-Michael Peters, Yves Pommier, Keith CaldecottKeith Caldecott, André NussenzweigTopoisomerase 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.
History
Publication status
- Published
File Version
- Accepted version
Journal
Molecular CellISSN
1097-2765Publisher
ElsevierExternal DOI
Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-07-22First Open Access (FOA) Date
2020-06-12First Compliant Deposit (FCD) Date
2019-07-22Usage metrics
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