title: Essential Roles of the Smc5/6 Complex in Replication through Natural Pausing Sites and Endogenous DNA Damage Tolerance.
abstract: The essential functions of the conserved Smc5/6 complex remain elusive. To uncover its roles in genome maintenance, we established Saccharomyces cerevisiae cell-cycle-regulated alleles that enable restriction of Smc5/6 components to S or G2/M. Unexpectedly, the essential functions of Smc5/6 segregated fully and selectively to G2/M. Genetic screens that became possible with generated alleles identified processes that crucially rely on Smc5/6 specifically in G2/M: metabolism of DNA recombination structures triggered by endogenous replication stress, and replication through natural pausing sites located in late-replicating regions. In the first process, Smc5/6 modulates remodeling of recombination intermediates, cooperating with dissolution activities. In the second, Smc5/6 prevents chromosome fragility and toxic recombination instigated by prolonged pausing and the fork protection complex, Tof1-Csm3. Our results thus dissect Smc5/6 essential roles and reveal that combined defects in DNA damage tolerance and pausing site-replication cause recombination-mediated DNA lesions, which we propose to drive developmental and cancer-prone disorders.
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.
authors.forename: Demis
authors.initials: D
authors.lastname: Menolfi
authors.affiliation: IGH, Institute of Human Genetics CNRS UPR 1142, 141 rue de la Cardonille F-34396 Cedex 5, Montpellier, France.
authors.forename: Axel
authors.initials: A
authors.lastname: Delamarre
authors.affiliation: IGH, Institute of Human Genetics CNRS UPR 1142, 141 rue de la Cardonille F-34396 Cedex 5, Montpellier, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Lengronne
authors.affiliation: IGH, Institute of Human Genetics CNRS UPR 1142, 141 rue de la Cardonille F-34396 Cedex 5, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pasero
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy. Electronic address: dana.branzei@ifom.eu.
authors.forename: Dana
authors.initials: D
authors.lastname: Branzei
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D004271:DNA, Fungal / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D020043:Genes, Essential; D005820:Genetic Testing; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C508610:Csm3p protein, S cerevisiae; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; C486627:SMC5 protein, S cerevisiae; C486631:SMC6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C119636:TOF1 protein, S cerevisiae