title: The Cohesin Complex Prevents the End Joining of Distant DNA Double-Strand Ends.
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.
authors.affiliation: 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.
authors.forename: Camille
authors.initials: C
authors.lastname: Gelot
authors.affiliation: 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.
authors.forename: Josée
authors.initials: J
authors.lastname: Guirouilh-Barbat
authors.affiliation: 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.
authors.forename: Tangui
authors.initials: T
authors.lastname: Le Guen
authors.affiliation: 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.
authors.forename: Elodie
authors.initials: E
authors.lastname: Dardillac
authors.affiliation: Université de Toulouse UPS, CNRS UMR 5088, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 31062 Toulouse, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chailleux
authors.affiliation: Université de Toulouse UPS, CNRS UMR 5088, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 31062 Toulouse, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Canitrot
authors.affiliation: 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.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints; D015321:Gene Rearrangement; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D059807:S Phase Cell Cycle Checkpoints; D013997:Time Factors; D014162:Transfection; D000097722:Cohesins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D015252:Deoxyribonucleases, Type II Site-Specific; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000097722:Cohesins; C500695:CDCA5 protein, human; C429022:RAD21 protein, human
keywords: NHEJ; cohesin; double-strand break repair; genome rearrangements; replication stress