The copper-sensing transcription factor Mac1, the histone deacetylase Hst1, and nicotinic acid regulate de novo NAD⁺ biosynthesis in budding yeast.

NADH (NAD⁺) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD⁺ metabolism is incompletely understood. Here, using budding yeast (Saccharomyces cerevisiae), we established an NAD⁺ intermediate-specific genetic system to identify factors that regulate the de novo branch of NAD⁺ biosynthesis. We found that a mutant strain (mac1Δ) lacking Mac1, a copper-sensing transcription factor that activates copper transport genes during copper deprivation, exhibits increases in quinolinic acid (QA) production and NAD⁺ levels. Similar phenotypes were also observed in the hst1Δ strain, deficient in the NAD⁺-dependent histone deacetylase Hst1, which inhibits de novo NAD⁺ synthesis by repressing BNA gene expression when NAD⁺ is abundant. Interestingly, the mac1Δ and hst1Δ mutants shared a similar NAD⁺ metabolism-related gene expression profile, and deleting either MAC1 or HST1 de-repressed the BNA genes. ChIP experiments with the BNA2 promoter indicated that Mac1 works with Hst1-containing repressor complexes to silence BNA expression. The connection of Mac1 and BNA expression suggested that copper stress affects de novo NAD⁺ synthesis, and we show that copper stress induces both BNA expression and QA production. Moreover, nicotinic acid inhibited de novo NAD⁺ synthesis through Hst1-mediated BNA repression, hindered the reuptake of extracellular QA, and thereby reduced de novo NAD⁺ synthesis. In summary, we have identified and characterized novel NAD⁺ homeostasis factors. These findings will expand our understanding of the molecular basis and regulation of NAD⁺ metabolism.

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