The Sirtuins Hst3 and Hst4p Preserve Genome Integrity by Controlling Histone H3 Lysine 56 Deacetylation

• DOI: 10.1016/j.cub.2006.06.023
• Publication Date: 2006-07-08T00:47:15Z
• Authors: Ivana Celic; Hiroshi Masumoto; Wendell P. Griffith; Pamela Meluh; Robert J. Cotter; Jef D. Boeke; Alain Verreault
• Keywords: DNA Replication; Niacinamide; 0301 basic medicine; Saccharomyces cerevisiae Proteins; Molecular Sequence Data; Cell Cycle Proteins; Saccharomyces cerevisiae; Genomic Instability; Histone Deacetylases; Histones; 03 medical and health sciences; Amino Acid Sequence; 0303 health sciences; Binding Sites; Agricultural and Biological Sciences(all); Biochemistry, Genetics and Molecular Biology(all); Lysine; Cell Cycle; Acetylation; DNA; Chromatin; Mutation; Genome, Fungal; Protein Processing, Post-Translational; DNA Damage; Molecular Chaperones

Acetylation of histone H3 lysine 56 (K56Ac) occurs transiently in newly synthesized H3 during passage through S phase and is removed in G2. However, the physiologic roles and effectors of K56Ac turnover are unknown.The sirtuins Hst3p and, to a lesser extent, Hst4p maintain low levels of K56Ac outside of S phase. In hst3 hst4 mutants, K56 hyperacetylation nears 100%. Residues corresponding to the nicotinamide binding pocket of Sir2p are essential for Hst3p function, and H3 K56 deacetylation is inhibited by nicotinamide in vivo. Rapid inactivation of Hst3/Hst4p prior to S phase elevates K56Ac to 50% in G2, suggesting that K56-acetylated nucleosomes are assembled genome-wide during replication. Inducible expression of Hst3p in G1 or G2 triggers deacetylation of mature chromatin. Cells lacking Hst3/Hst4p exhibit many phenotypes: spontaneous DNA damage, chromosome loss, thermosensitivity, and acute sensitivity to genotoxic agents. These phenotypes are suppressed by mutation of histone H3 K56 into a nonacetylatable residue or by loss of K56Ac in cells lacking the histone chaperone Asf1.Our results underscore the critical importance of Hst3/Hst4p in controlling histone H3 K56Ac and thereby maintaining chromosome integrity.