Session 4 : Molecular mechanisms of resistance

Chromosome and chromatin dynamics during Transcription-coupled DSB repair

Abstract

DNA double-strand break repair is an essential process ensuring the maintenance of genome integrity and recently, a transcription-coupled arm of DSB repair has been identified (named TC-DSBR for Transcription-Coupled DSB Repair).

Using a cell line, called DIvA (for DSB Inducible via AsiSI), where multiples breaks are induced at annotated positions, combined with genome-wide, high throughput sequencing based techniques (ChIP-seq, HiC...) we investigate the contribution of chromatin and chromosome conformation in the response to TC-DSB, induced in transcriptionally active loci. I will present our recent work, on the contribution of chromatin and Topologically Associating Domains (TADs) during DSB repair. More specifically we recently demonstrated the role of cohesin-mediated loop extrusion in establishing gammaH2AX on an entire TAD in cis to DSBs. We further provided evidence that when established, gammaH2AX “tagged” TAD further self-segregate in the nucleus, forming a novel DSB-induced chromatin compartment (the “D” compartment) that contributes to the activation of the DNA damage response. Finally, we recently identified the PER complex, a molecular device ensuring circadian oscillations, as a key component of TC-DSB Repair through a previously unsuspected role in positioning DSBs at the periphery of the nucleus.

 

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation