The Cohesin Complex Prevents the End Joining of Distant DNA Double-Strand Ends

The end joining of distant DNA double-strand ends (DSEs) can produce potentially deleterious rearrangements. We show that depletion of cohesion complex proteins specifically stimulates the end joining (both C-NHEJ and A-EJ) of distant, but not close, I-SceI-induced DSEs in S/G2 phases. At the genome level, whole-exome sequencing showed that ablation of RAD21 or Sororin produces large chromosomal rearrangements (translocation, duplication, deletion). Moreover, cytogenetic analysis showed that RAD21 silencing leads to the formation of chromosome fusions synergistically with replication stress, which generates distant single-ended DSEs. These data reveal a role for the cohesin complex in protecting against genome rearrangements arising from the ligation of distant DSEs in S/G2 phases (both long-range DSEs and those that are only a few kilobases apart), while keeping end joining fully active for close DSEs. Therefore, this role likely involves limitation of DSE motility specifically in S phase, rather than inhibition of the end-joining machinery itself. [Display omitted] •Cohesin complex represses the end joining of distant DNA ends in the S/G2 phases•Cohesin complex represses both C-NHEJ and A-EJ of distant, but not close, DNA ends•Cohesin complex prevents large chromosomal rearrangements•Cohesin complex protects against replication stress-induced chromosome rearrangements Gelot et al. show that the cohesin complex specifically represses in the S/G2 phases, both C-NHEJ and A-EJ of DNA ends that are few kilobases (3.2) apart, without affecting the joining of close ends. Consistently, the cohesin complex protects against intra- and interchromosomal rearrangements induced by a replication stress.