Molecular Cell
Volume 75, Issue 2, 25 July 2019, Pages 252-266.e8
Journal home page for Molecular Cell

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

https://doi.org/10.1016/j.molcel.2019.04.030Get rights and content
Under an Elsevier user license
open archive

Highlights

  • TOP2 binding and cleavage complex (TOP2cc) formation is dependent on cohesin

  • Transcription facilitates the processing of TOP2cc to DSBs that drives translocation

  • TOP2cc processing is rapid, while commitment to processing is rate-limiting

  • Cohesin and transcription levels predict TOP2-mediated breakage and translocation

Summary

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.

Keywords

topoisomerase
topoisomerase 2 cleavage complex
DNA double-strand breaks
cohesin
3D chromatin organization
transcription
chromosomal translocations
proteasome
TDP2
quantitative modeling

Cited by (0)

7

These authors contributed equally

8

Lead Contact