title: Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination.
abstract: During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage. Mimicking constitutive acetylation stimulates homologous recombination and robustly suppresses the DNA damage sensitivity of mutations in damage tolerance pathways. In comparison to the unmodified trimer, structural differences are observed at the interface between protomers in the crystal structure of the PCNA-K20ac ring. Thus, acetylation regulates PCNA sliding on DNA in the presence of DNA damage, favoring homologous recombination linked to sister-chromatid cohesion.
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Centre de Recherche du CHU de Québec-Axe Oncologie, Quebec City, QC G1R 3S3, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billon
authors.affiliation: Department of Biological Sciences and Molecular and Cellular Biology Graduate Program, Ohio University, Athens, OH 45701, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: Department of Biological Sciences and Molecular and Cellular Biology Graduate Program, Ohio University, Athens, OH 45701, USA.
authors.forename: Yizhang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Tremblay
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Brunzelle
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Institute for Research in Immunology and Cancer and Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Verreault
authors.affiliation: Department of Biological Sciences and Molecular and Cellular Biology Graduate Program, Ohio University, Athens, OH 45701, USA.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Couture
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Centre de Recherche du CHU de Québec-Axe Oncologie, Quebec City, QC G1R 3S3, Canada. Electronic address: jacques.cote@crhdq.ulaval.ca.
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002842:Chromatids; D015825:Chromosomes, Fungal; D004249:DNA Damage; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D008239:Lysine; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D059767:Recombinational DNA Repair; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D009687:Nuclear Proteins; C546594:POL30 protein, S cerevisiae; D018809:Proliferating Cell Nuclear Antigen; D029701:Saccharomyces cerevisiae Proteins; D000123:Acetyltransferases; C118076:ECO1 protein, S cerevisiae; D004258:DNA Polymerase III; D008239:Lysine
keywords: DNA polymerases; Eco1; PCNA; homologous recombination; lysine acetylation; translesion synthesis