title: Interplay between histone H3 lysine 56 deacetylation and chromatin modifiers in response to DNA damage.
abstract: In Saccharomyces cerevisiae, histone H3 lysine 56 acetylation (H3K56Ac) is present in newly synthesized histones deposited throughout the genome during DNA replication. The sirtuins Hst3 and Hst4 deacetylate H3K56 after S phase, and virtually all histone H3 molecules are K56 acetylated throughout the cell cycle in hst3∆ hst4∆ mutants. Failure to deacetylate H3K56 causes thermosensitivity, spontaneous DNA damage, and sensitivity to replicative stress via molecular mechanisms that remain unclear. Here we demonstrate that unlike wild-type cells, hst3∆ hst4∆ cells are unable to complete genome duplication and accumulate persistent foci containing the homologous recombination protein Rad52 after exposure to genotoxic drugs during S phase. In response to replicative stress, cells lacking Hst3 and Hst4 also displayed intense foci containing the Rfa1 subunit of the single-stranded DNA binding protein complex RPA, as well as persistent activation of DNA damage-induced kinases. To investigate the basis of these phenotypes, we identified histone point mutations that modulate the temperature and genotoxic drug sensitivity of hst3∆ hst4∆ cells. We found that reducing the levels of histone H4 lysine 16 acetylation or H3 lysine 79 methylation partially suppresses these sensitivities and reduces spontaneous and genotoxin-induced activation of the DNA damage-response kinase Rad53 in hst3∆ hst4∆ cells. Our data further suggest that elevated DNA damage-induced signaling significantly contributes to the phenotypes of hst3∆ hst4∆ cells. Overall, these results outline a novel interplay between H3K56Ac, H3K79 methylation, and H4K16 acetylation in the cellular response to DNA damage.
authors: Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada H1T 2M4.
authors: Antoine
authors: A
authors: Simoneau
authors: Institute for Research in Immunology and Cancer, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7.
authors: Neda
authors: N
authors: Delgoshaie
authors: High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors: Ivana
authors: I
authors: Celic
authors: High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 School of Life Sciences, Tsinghua University, Beijing, China 100084.
authors: Junbiao
authors: J
authors: Dai
authors: Institute for Research in Immunology and Cancer, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7 Département de Chimie, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7.
authors: Nebiyu
authors: N
authors: Abshiru
authors: Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada H1T 2M4 Département d'ophtalmologie, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7.
authors: Santiago
authors: S
authors: Costantino
authors: Institute for Research in Immunology and Cancer, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7 Département de Chimie, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7.
authors: Pierre
authors: P
authors: Thibault
authors: High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York 10016.
authors: Jef D
authors: JD
authors: Boeke
authors: Institute for Research in Immunology and Cancer, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7 Département de Pathologie et Biologie Cellulaire, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7.
authors: Alain
authors: A
authors: Verreault
authors: Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada H1T 2M4 Département de Médecine, Université de Montréal, Succursale Centre-Ville, Montreal, QC, Canada H3C 3J7 hugo.wurtele@umontreal.ca.
authors: Hugo
authors: H
authors: Wurtele
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D011499:Protein Processing, Post-Translational; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; C497197:RAD52 protein, S cerevisiae; C082728:RFA1 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D051716:Replication Protein A; D029701:Saccharomyces cerevisiae Proteins; D064447:Checkpoint Kinase 2; C067022:RAD53 protein, S cerevisiae; C512517:Hst3 protein, S cerevisiae; C512518:Hst4 protein, S cerevisiae; D006655:Histone Deacetylases
keywords: DNA damage repair and checkpoint response; H3 lysine 56 acetylation; H3 lysine 79 methylation; H4 lysine 16 acetylation; chromatin structure