Journal
NUCLEIC ACIDS RESEARCH
Volume 44, Issue 6, Pages 2706-2726Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv1537
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Funding
- Canadian Institutes of Health Research [MOP 123438]
- Cole Foundation
- Canadian Foundation for Innovation
- Merieux Institute
- Canadian Cancer Society Research Institute [20380]
- National Human Genome Research Institute
- Fonds de la recherche du Quebec-Sante
- Canadian Institutes for Health Research [MOP 123438]
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The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1-4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3 Delta hst4 Delta double mutants are exquisitely sensitive to genotoxins, and hst3 Delta hst4 Delta sir2 Delta mutants are inviable. Our published data also indicate that pharmacological inhibition of sirtuins prevents growth of several fungal pathogens, although the biological basis is unclear. Here, we present genome-wide fitness assays conducted with nicotinamide (NAM), a pan-sirtuin inhibitor. Our data indicate that NAM treatment causes yeast to solicit specific DNA damage response pathways for survival, and that NAM-induced growth defects are mainly attributable to inhibition of Hst3 and Hst4 and consequent elevation of histone H3 lysine 56 acetylation (H3K56ac). Our results further reveal that in the presence of constitutive H3K56ac, the Slx4 scaffolding protein and PP4 phosphatase complex play essential roles in preventing hyperactivation of the DNA damage-response kinase Rad53 in response to spontaneous DNA damage caused by reactive oxygen species. Overall, our data support the concept that chromosome-wide histone deacetylation by sirtuins is critical to mitigate growth defects caused by endogenous genotoxins.
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