Oral Presentation 41st Lorne Genome Conference 2020

Chromosome and chromatin dynamics at DNA Double Strand break (#8)

Gaëlle Legube 1
  1. Centre de Biologie Intégrative, University of Toulouse, Toulouse, France

DNA double-strand breaks (DSBs) are highly toxic lesions that are rapidly repaired by two main pathways, namely Homologous Recombination (HR) and Non Homologous End Joining (NHEJ). Using a cell line, called DIvA (for DSB Inducible via AsiSI), where multiples breaks can be induced at annotated positions throughout the human genome, we previously reported that DSBs induced in transcriptionally active genes are channeled to HR during G2, thanks to a chromatin dependent signaling, while DSB occurring in intergenic regions rather undergo NHEJ (1). Using Capture Hi-C and super resolution microscopy, we further reported that these DSBs induced in active genes undergo clustering in an ATM dependent manner (2) and mostly during G1 (3). Notably, clustering coincides with delayed repair in G1 (3). Collectively our data suggest that when damaged, transcriptionally active units adopt a very peculiar behavior, being repaired by HR in G2 and left unrepaired and clustered in G1. More recently, using this cell line, we have investigated, using ChIP-seq (4) and Hi-C, 4C-seq the chromatin structure assembled around DSBs. This allowed us to unveil basic principles of chromatin structure dynamics occurring at DSBs and to identify Topologically Associating Domains (TADs) as functional units during DSB repair.

This project DIvA has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 647344).

  1. Aymard et al, Transcriptionally active chromatin channels DNA double strand breaks to homologous recombination. Nature structural & molecular biology. 2014 21(4):366-74
  2. Caron et al, Non redundant functions of ATM and DNAPK in response to DNA Double-Strand Breaks. Cell Reports. 2015 Nov 24;13(8):1598-609
  3. Aymard et al, Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes. Nature structural & molecular biology. 2017 24(4):353-61
  4. Clouaire et al, Comprehensive histone modification mapping at DNA Double Strand Breaks deciphers repair pathway histone codes. Mol Cell, 2018 Oct 18;72(2):250-262.