Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro bench research using Saccharomyces cerevisiae
PubMed 26748095 · doi:10.1093/nar/gkv1537
What was done
Genome-wide fitness assays were performed in Saccharomyces cerevisiae treated with the pan-sirtuin inhibitor nicotinamide (NAM) to investigate the mechanisms by which sirtuin inhibition impairs fungal growth and causes genotoxin sensitivity.
What was found
The abstract reports no numerical values. Qualitatively, NAM-induced growth defects were primarily driven by the inhibition of Hst3 and Hst4 and the resulting increase in histone H3 lysine 56 acetylation (H3K56ac). Under constitutive H3K56ac, the Slx4 scaffolding protein and the PP4 phosphatase complex were required to prevent hyperactivation of the DNA damage-response kinase Rad53 triggered by endogenous reactive oxygen species.
Why it matters
This study delineates the molecular pathway connecting sirtuin-mediated histone deacetylation to the regulation of DNA damage signaling under endogenous replicative stress, clarifying why sirtuin inhibitors inhibit fungal growth.
Limits
The abstract provides no quantitative metrics or effect sizes. Findings are restricted to the model organism Saccharomyces cerevisiae and require validation in pathogenic fungal species and higher eukaryotes.
Cited by
- supports Humans have seven sirtuin enzymes (SIRT1 through SIRT7), whereas yeast have five sirtuins.