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

Mol Cell. 2016 Jan 7;61(1):15-26. doi: 10.1016/j.molcel.2015.11.002. Epub 2015 Dec 10.


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.

Keywords: NHEJ; cohesin; double-strand break repair; genome rearrangements; replication stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosome Aberrations
  • DNA Breaks, Double-Stranded*
  • DNA Repair*
  • DNA Replication*
  • DNA-Binding Proteins
  • Deoxyribonucleases, Type II Site-Specific / genetics
  • Deoxyribonucleases, Type II Site-Specific / metabolism
  • G2 Phase Cell Cycle Checkpoints
  • Gene Rearrangement
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA Interference
  • S Phase Cell Cycle Checkpoints
  • Time Factors
  • Transfection


  • Adaptor Proteins, Signal Transducing
  • CDCA5 protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • RAD21 protein, human
  • cohesins
  • Deoxyribonucleases, Type II Site-Specific