Cohesin activity accelerates the homology search

Homologous recombination (HR) repair preserves genome integrity in post-replicative cells by orchestrating templated repair of DNA double-strand breaks (DSBs). A critical stage of HR is the homology search, the process by which the DSB is brought in contact with a repair template, which is often the replicated locus. Using molecular dynamics simulations, we model the mammalian homology search, with focus on the role of the chromatin architecture factor cohesin. Our simulations recapitulate key experimental findings, including the distribution of genomic loci interrogated by the DSB and the chromatin interactions that accompany the homology search. We show that cohesin-mediated loop extrusion greatly accelerates the search process, and this effect is further enhanced by anchoring loop-extruding cohesin at DSB sites and recruiting a cohesive cohesin clamp that stabilizes DSB-sister chromatid interactions. We reveal that cohesin's contribution to accelerating the search scales linearly with TAD size and becomes more pronounced when breaks occur in large TADs. We also show that chromatin loops along the broken and the sister chromatid play different roles in the search: the former establish initial contact between the break site and sister chromatid, whereas the latter promote scanning along the sister chromatid. Our findings indicate that coordinated activity of loop-extruding and cohesive cohesin transforms the homology search from 3D diffusion into a fast 1D scanning process.