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

• Published in: Current biology 2006-07, Vol.16 (13), p.1280-1289
• Main Authors: Celic, Ivana, Masumoto, Hiroshi, Griffith, Wendell P., Meluh, Pamela, Cotter, Robert J., Boeke, Jef D., Verreault, Alain
• Format: Article
• Language: English
• Subjects: Acetylation; Amino Acid Sequence; Binding Sites; Cell Cycle - physiology; Cell Cycle Proteins - physiology; Chromatin - metabolism; DNA; DNA Damage; DNA Replication; Genome, Fungal; Genomic Instability; Histone Deacetylases - chemistry; Histone Deacetylases - genetics; Histone Deacetylases - physiology; Histones - metabolism; Lysine - metabolism; Molecular Chaperones; Molecular Sequence Data; Mutation; Niacinamide - metabolism; Protein Processing, Post-Translational; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - physiology; Sequence Alignment; Sirtuins - chemistry; Sirtuins - genetics; Sirtuins - physiology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2006.06.023

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.