title: Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage.
abstract: Mammalian cells deficient in ATR or Chk1 display moderate replication fork slowing and increased initiation density, but the underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both replication phenotypes in Chk1-deficient, but not ATR-deficient, cells. Thus, in the absence of exogenous stress, depletion of either protein impacts the replication dynamics through different mechanisms. In addition, Chk1 deficiency, but not ATR deficiency, triggers nuclease-dependent DNA damage. Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. Damage and resulting DDR activation are therefore the cause, not the consequence, of replication dynamics modulation in these cells. Together, we identify moderate reduction of precursors available for replication as an additional outcome of DDR activation. We propose that resulting fork slowing, and subsequent firing of backup origins, helps replication to proceed along damaged templates.
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Técher
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Koundrioukoff
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Carignon
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France.
authors.forename: Therese
authors.initials: T
authors.lastname: Wilhelm
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France.
authors.forename: Gaël A
authors.initials: GA
authors.lastname: Millot
authors.affiliation: Institut de Cancérologie Gustave Roussy, CNRS UMR 8200 and Université Paris Sud, 94805 Villejuif, France.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Brison
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3244, 75248 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, 75252 Paris Cedex 05, France. Electronic address: michelle.debatisse@curie.fr.
authors.forename: Michelle
authors.initials: M
authors.lastname: Debatisse
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003853:Deoxyribonucleosides / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism*; D006801:Humans; D000076228:MRE11 Homologue Protein; D011494:Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D018741:Replication Origin; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D003853:Deoxyribonucleosides; C121766:MRE11 protein, human; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000588977:EME2 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D000076228:MRE11 Homologue Protein; C498772:MUS81 protein, human