DNA double-strand break (DSB) repair is essential for genome stability maintenance, but the joining of distant DNA double strand ends (DSEs) inevitably leads to genome rearrangements. Therefore, DSB repair should be tightly controlled to secure genome stability while allowing genetic variability. Tethering of the proximal ends of a 2-ended DSB limits their mobility, protecting thus against their joining with a distant DSE. However, replication stress generates DSBs with only one DSE, on which tethering is impossible. Consistently, we demonstrated that the joining of 2 DSBs only 3.2 kb apart is repressed in the S, but not the G1, phase, revealing an additional mechanism limiting DNA ends mobility in S phase. The cohesin complex, by maintaining the 2 sister chromatids linked, limits DSEs mobility and thus represses the joining of distant DSEs, while allowing that of adjacent DSEs. At the genome scale, the cohesin complex protects against deletions, inversions, translocations and chromosome fusion.
Keywords: Cohesin; NHEJ; double-strand breaks repair; genome rearrangements; replication stress.