title: Replisome function during replicative stress is modulated by histone h3 lysine 56 acetylation through Ctf4.
abstract: Histone H3 lysine 56 acetylation in Saccharomyces cerevisiae is required for the maintenance of genome stability under normal conditions and upon DNA replication stress. Here we show that in the absence of H3 lysine 56 acetylation replisome components become deleterious when replication forks collapse at natural replication block sites. This lethality is not a direct consequence of chromatin assembly defects during replication fork progression. Rather, our genetic analyses suggest that in the presence of replicative stress H3 lysine 56 acetylation uncouples the Cdc45-Mcm2-7-GINS DNA helicase complex and DNA polymerases through the replisome component Ctf4. In addition, we discovered that the N-terminal domain of Ctf4, necessary for the interaction of Ctf4 with Mms22, an adaptor protein of the Rtt101-Mms1 E3 ubiquitin ligase, is required for the function of the H3 lysine 56 acetylation pathway, suggesting that replicative stress promotes the interaction between Ctf4 and Mms22. Taken together, our results indicate that Ctf4 is an essential member of the H3 lysine 56 acetylation pathway and provide novel mechanistic insights into understanding the role of H3 lysine 56 acetylation in maintaining genome stability upon replication stress.
authors.affiliation: Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Luciano
authors.affiliation: Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Dehé
authors.affiliation: Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Audebert
authors.affiliation: Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Géli
authors.affiliation: Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France yves.corda@inserm.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Corda
mesh_terms: D000107:Acetylation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D000099272:Replisomes
chemical_list: D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D006657:Histones; D008239:Lysine; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D000099272:Replisomes; C102209:CDC45 protein, S cerevisiae; C078338:CTF4 protein, S cerevisiae; C530190:Mms1 protein, S cerevisiae; C497133:Mms22 protein, S cerevisiae; C476451:RTT101 protein, S cerevisiae
keywords: Ctf4; H3K56 acetylation; Mms22; replicative stress; replisome