Cohesin guides homology search during DNA repair using loops and sister chromatid linkages.

Abstract

Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequence to faithfully restore damaged DNA, yet how broken DNA ends find homologous sites in a genome containing billions of bases remains unclear. Here, we introduce sister-pore-C, a high-resolution method to map intra- and intermolecular interactions in replicated chromosomes. We show how DSBs remodel chromosome architecture using two functionally distinct pools of cohesin. Loop-extruding cohesin accumulates across megabase-scale domains surrounding DSBs to control local homology sampling, whereas cohesive cohesin concentrates at break sites to tether DNA ends to the sister chromatid. This mechanism restricts the homology-sampling space, highlighting how chromosome conformation helps to preserve genomic integrity.