Regulation of genomic stability by Saccharomyces cerevisiae sirtuins Hst3p and Hst4p
The Sir2 proteins, also known as sirtuins, represent a large and highly conserved family of NAD+-dependent protein deacetylases that control various fundamental biological proceses. The baker’s yeast, Saccharomyces cerevisiae, has five members of this family, Sir2p and Hst1-4p, important for regulation of transcriptional silencing and genomic stability. Hst3p and Hst4p are two redundant sirtuins with the major role in maintenance of genomic stablity. They control genomic stability by regulating the level of acetylation of histone H3 lysine 56. This residue, present in the core of the nucleosome surface, is acetylated during the S phase of the cel cycle and contributes to the repair proceses active during DNA replication. At the end of the S phase, K56 of histone H3 is deacetylated in a Hst3p- and Hst4p-dependent manner. Failure to deacetylate K56 leads to a growth defect, sensitivity to DNA-damaging agents and chromosome los in N cels. These phenotypes can be suppresed by mutation of K56 into the nonacetylable residue arginine. Failure to deacetylate K56 also leads to activation of the DNA-damage response and renders hst3 hst4 cels senstive to perturbations in DNA replication, repair and checkpoint function as is evident from numerous synthetic lethality interactions that hst3 hst4 cels display with mutations in the genes that regulate these proceses. The growth defect of hst3 hst4 cels can be suppresed by overexpresion of , the large subunit of RFC, a “clamp loader” that loads PCNA, the “sliding clamp” onto DNA during DNA replication. Interestingly, the growth defect of hst3 hst4 cels can also be suppresed by deletion of CTF18 and, somewhat les eficiently, RAD24 and and ELGI al encode large subunits of alternative RFCs, each of which shares four smaler subunits (Rfc2p-Rfc5p) with Rfc1p. We propose that ongoing cycles of K56 acetylation and deacetylation contribute to the regulation of the functional equlibrium between diferent RFC complexes in the cel.