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The deacetylase Sir2 is the primary sensor driving transcriptional changes in response to low NAD+ in the yeast Kluyveromyces lactis

ABSTRACT: The coenzyme NAD+ (nicotinamide adenine dinucleotide) is a critical electron carrier in central metabolism and is required for cellular health. It is proposed that cells sense intracellular NAD+ levels using sirtuin deacetylases, which require NAD+ for their enzymatic activity. We tested this hypothesis by examining how intracellular NAD+ levels affect expression of Sir2-repressed genes in the yeast Kluyveromyces lactis. Because K. lactis cannot synthesize NAD+, we could create a gradient of intracellular NAD+ levels by growing cells in varying concentrations of the precursor nicotinic acid. We found that as NAD+ levels decreased, acetylation of histones at target promoters increased, as did expression of these genes. RNA-Seq analysis revealed that genes induced in low nicotinic acid include some that would restore NAD+ levels, such as the high-affinity nicotinic acid transporter TNA1, and some that would enable long term survival, such as genes promoting sporulation. Most genes induced in low nicotinic acid (100 of 114 or 88%) were also induced in the absence of Sir2. Moreover, in sir2Δ cells, few transcriptional changes occurred in response to low nicotinic acid. Thus, Sir2 is the primary sensor responsible for the transcriptional response to low NAD+ in K. lactis. In addition, the degree of induction varied across NAD+ levels, suggesting that Sir2 behaves as a rheostat, tuning gene expression to NAD+ availability.

ORGANISM(S): Kluyveromyces lactis

PROVIDER: GSE303949 | GEO | 2026/01/22

REPOSITORIES: GEO

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