Cohesin drives chromatin scanning during the RAD51-mediated homology search

Abstract

Cohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop base positioned at the DSB site. These loops form in the S and G₂ phases of the cell cycle during homologous recombination repair, concomitantly with DNA end resection and radiation-sensitive protein 51 (RAD51) recruitment. RAD51 shows a broad (megabase-sized) chromatin domain reflective of the homology search. This domain is regulated by cohesin unloader and overlaps with chromatin regions reeled through the break-anchored loop, suggesting that loop extrusion regulates the homology search. Indeed, depletion of the loop-extruding cohesin subunit NIPBL lowers homologous recombination in mouse embryonic stem cells, and this effect is more pronounced when the homologous recombination donor is hundreds of kilobases from the DSB. Our data indicate that loop-extruding cohesin promotes the mammalian homology search by facilitating break-chromatin interactions.