HST1 increases replicative lifespan of a sir2Δ mutant in the absence of PDE2 in Saccharomyces cerevisiae.

Silent information regulator 2 (Sir2), which is the founding member of the sirtuin family of proteins, is a pro-longevity factor for replicative lifespan (RLS) in Saccharomyces cerevisiae. Sir2 is required for transcriptional silencing at mating type loci, telomeres, and rDNA loci. Sir2 also represses transcription of highly expressed growth-related genes, such as PMA1 and some ribosomal protein genes. Although the Sir2 paralogues Hst1, Hst2, Hst3, and Hst4 occur in S. cerevisiae, none of them could replace the transcriptional regulation of PMA1 by Sir2 in the wild type. In this study, we demonstrate that Hst1, the closest Sir2 paralogue, deacetylates the acetylated lysine 16 of histone H4 (H4K16Ac) and represses PMA1 transcription in the sir2Δ pde2Δ mutant. We further show that Hst1 plays a role in extending the RLS of the sir2Δ pde2Δ mutant. Collectively, our results suggest that Hst1 can substitute for Sir2 by deacetylating H4K16Ac only in the sir2Δ pde2Δ.