Topoisomerase II-induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity
Dr Andre NUSSENZWEIG
NIH, Laboratory of genome integrity, United States
Friday, May 17th 2019 - 11 a.m.
- Auditorium, IGBMC
Hosted by Bernardo REINA SAN MARTIN & Evi SOUTOGLOU
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 twofold 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.