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

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

Author information

1
Centre National de la Recherche Scientifique (CNRS) UMR 8200, Institut de Cancérologie Gustave-Roussy, Université Paris-Saclay, Equipe Labellisée Ligue Contre le Cancer, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
2
Université de Toulouse UPS, CNRS UMR 5088, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 31062 Toulouse, France.
3
Centre National de la Recherche Scientifique (CNRS) UMR 8200, Institut de Cancérologie Gustave-Roussy, Université Paris-Saclay, Equipe Labellisée Ligue Contre le Cancer, 114 Rue Edouard Vaillant, 94805 Villejuif, France. Electronic address: bernard.lopez@gustaveroussy.fr.

Abstract

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

PMID:
26687679
DOI:
10.1016/j.molcel.2015.11.002
[Indexed for MEDLINE]
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