Cohesin guides homology search during DNA repair via loops and sister chromatid linkages
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 inter-molecular interactions in replicated chromosomes. We show how DSBs remodel chromosome architecture by two functionally distinct pools of cohesin. Loop-extruding cohesin accumulates across megabase-scale domains surrounding DSBs to control local homology sampling, while 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 preserve genomic integrity.
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 inter-molecular interactions in replicated chromosomes. We show how DSBs remodel chromosome architecture by two functionally distinct pools of cohesin. Loop-extruding cohesin accumulates across megabase-scale domains surrounding DSBs to control local homology sampling, while 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 preserve genomic integrity.
Institute of Molecular Biotechnology