TY - JOUR
T1 - The Sirtuins Hst3 and Hst4p Preserve Genome Integrity by Controlling Histone H3 Lysine 56 Deacetylation
AU - Celic, Ivana
AU - Masumoto, Hiroshi
AU - Griffith, Wendell P.
AU - Meluh, Pamela
AU - Cotter, Robert J.
AU - Boeke, Jef D.
AU - Verreault, Alain
N1 - Funding Information:
We thank Hidekazu Takashi for yeast strains and Rohinton Kamakaka and David Toczyski for sharing results prior to publication. H.M. thanks Prof. Akio Sugino for laboratory space and reagents. H.M.'s research was supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Research in A.V.'s laboratory was funded by Cancer Research UK, the Association for International Cancer Research (AICR) and the Canadian Institutes for Health Research (CIHR). Research in J.D.B. and R.J.C.'s laboratories was funded by NIH grant GM62385 and NIH Roadmap grant RR020839.
PY - 2006/7/11
Y1 - 2006/7/11
N2 - Background: 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. Results: 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. Conclusions: Our results underscore the critical importance of Hst3/Hst4p in controlling histone H3 K56Ac and thereby maintaining chromosome integrity.
AB - Background: 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. Results: 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. Conclusions: Our results underscore the critical importance of Hst3/Hst4p in controlling histone H3 K56Ac and thereby maintaining chromosome integrity.
KW - DNA
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U2 - 10.1016/j.cub.2006.06.023
DO - 10.1016/j.cub.2006.06.023
M3 - Article
C2 - 16815704
AN - SCOPUS:33745520486
SN - 0960-9822
VL - 16
SP - 1280
EP - 1289
JO - Current Biology
JF - Current Biology
IS - 13
ER -