Journal
MOLECULAR CELL
Volume 75, Issue 2, Pages 252-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.04.030
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Funding
- Intramural Program of the NIH, Center for Cancer Research [Z01 BC006161]
- Boehringer Ingelheim
- Austrian Research Promotion Agency [FFG-834223FFG-852936]
- European Research Council H2020 [693949]
- Kyoto University Hakubi Project
- Intramural Research Program of the NIH
- Ellison Medical Foundation Senior Scholar in Aging Award [AG-SS-2633-11]
- Department of Defense Idea Expansion Award [W81XWH-15-2-006]
- Alex Lemonade Stand Foundation Award
- NIH Intramural FLEX Award
- Department of Defense Breakthrough Award [W81XWH-16-1-599]
- NATIONAL CANCER INSTITUTE [ZIABC010959] Funding Source: NIH RePORTER
- European Research Council (ERC) [693949] Funding Source: European Research Council (ERC)
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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.
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