title: Hst3p, a histone deacetylase, promotes maintenance of Saccharomyces cerevisiae chromosome III lacking efficient replication origins.
abstract: Long gaps between active replication origins probably occur frequently during chromosome replication, but little is known about how cells cope with them. To address this issue, we deleted replication origins from S. cerevisiae chromosome III to create chromosomes with long interorigin gaps and identified mutations that destabilize them [originless fragment maintenance (Ofm) mutations]. ofm6-1 is an allele of HST3, a sirtuin that deacetylates histone H3K56Ac. Hst3p and Hst4p are closely related, but hst4Δ does not cause an Ofm phenotype. Expressing HST4 under the control of the HST3 promoter suppressed the Ofm phenotype of hst3Δ, indicating Hst4p, when expressed at the appropriate levels and/or at the correct time, can fully substitute for Hst3p in maintenance of ORIΔ chromosomes. H3K56Ac is the Hst3p substrate critical for chromosome maintenance. H3K56Ac-containing nucleosomes are preferentially assembled into chromatin behind replication forks. Deletion of the H3K56 acetylase and downstream chromatin assembly factors suppressed the Ofm phenotype of hst3, indicating that persistence of H3K56Ac-containing chromatin is deleterious for the maintenance of ORIΔ chromosomes, and experiments with synchronous cultures showed that it is replication of H3K56Ac-containing chromatin that causes chromosome loss. This work shows that while normal chromosomes can tolerate hyperacetylation of H3K56Ac, deacetylation of histone H3K56Ac by Hst3p is required for stable maintenance of a chromosome with a long interorigin gap. The Ofm phenotype is the first report of a chromosome instability phenotype of an hst3 single mutant.
authors: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, ICPH, 225 Warren St., Newark, NJ, 07101-1701, USA.
authors: Carmela
authors: C
authors: Irene
authors: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, ICPH, 225 Warren St., Newark, NJ, 07101-1701, USA.
authors: James F
authors: JF
authors: Theis
authors: Department of Biology, Center for Genomics and System Biology, New York University, 100 Washington Square East, New York, NY, 10003, USA.
authors: David
authors: D
authors: Gresham
authors: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, ICPH, 225 Warren St., Newark, NJ, 07101-1701, USA.
authors: Patricia
authors: P
authors: Soteropoulos
authors: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, ICPH, 225 Warren St., Newark, NJ, 07101-1701, USA. newlon@njms.rutgers.edu.
authors: Carol S
authors: http://orcid.org/0000-0003-1617-2061
authors: CS
authors: Newlon
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics; D015825:Chromosomes, Fungal / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics*; D006657:Histones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D018741:Replication Origin / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; C512517:Hst3 protein, S cerevisiae; D006655:Histone Deacetylases
keywords: DNA replication; Genome stability; Histone H3 K56 acetylation; SNP analysis; Sirtuin