During this project, we investigated the contribution of chromatin during the response to DNA Double strand break.
First we found that pre-establish chromatin is a key determinant for the repair process. Indeed, altogether our work revealed that when damaged, active genes exhibit a very peculiar behavior compared to the rest of the genome and undergo a specific repair pathway that we named TC-DSBR (Transcription Coupled DSB Repair). We wrote a number of reviews to discuss this novel pathway (Clouaire et al., 2017; Marnef and Legube, 2017; Marnef et al., 2017; Puget et al., 2019). In brief, we found that these DSB induced in active genes, are clustered and mostly left unrepaired during the G1 phase of the cell cycle (Caron et al, 2015, Aymard et al, 2017) and are repaired by homologous recombination in G2, in a manner that involves the Senataxin RNA:DNA helicase (Cohen et al, 2018). Deficiency of this pathway enhances translocations frequency (Cohen et al, 2018). Moreover, we also reported new insights on how DSB occurring on the most transcribed part of our genome, i.e. the ribosomal DNA, are repaired. Unexpectedly we discovered that the nuclear envelope is somehow involved in this repair process, and identified a chromatin modifying complex (the HUSH complex) as involved in ribosomal break repair (Marnef et al, 2019).
Second, during this project we provided the most comprehensive view of the chromatin structure that is induced around DSBs: We described the chromatin landscape induced at DSBs, and identified a “repair histone code” (Clouaire et al, 2018). We also reported how chromosome folding is modified post break induction using chromosome conformation capture, followed by high throughput sequencing. This allowed us to discover that chromosome folding, and more specifically the process of “loop extrusion” is instrumental for the formation of the DNA Damage response foci (Arnould et al, 2021).
