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J Biol Chem. 2019 Apr 5;294(14):5562-5575. doi: 10.1074/jbc.RA118.006987. Epub 2019 Feb 13.

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

Author information

1
From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
2
From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616 slin@ucdavis.edu.

Abstract

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.

KEYWORDS:

NAD+ biosynthesis; cell metabolism; epigenetics; gene regulation; histone deacetylase; metabolic regulation; metal sensing; nicotinamide adenine dinucleotide (NAD); nicotinic acid; yeast genetics; yeast metabolism

PMID:
30760525
PMCID:
PMC6462523
[Available on 2020-04-05]
DOI:
10.1074/jbc.RA118.006987

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