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Molecular and Cellular Biology, October 2003, p. 7044-7054, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.7044-7054.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

NAD⁺-Dependent Deacetylase Hst1p Controls Biosynthesis and Cellular NAD⁺ Levels in Saccharomyces cerevisiae

Clinical Research and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Received 16 May 2003/ Returned for modification 23 June 2003/ Accepted 7 July 2003

Nicotine adenine dinucleotide (NAD⁺) performs key roles in electron transport reactions, as a substrate for poly(ADP-ribose) polymerase and NAD⁺-dependent protein deacetylases. In the latter two processes, NAD⁺ is consumed and converted to ADP-ribose and nicotinamide. NAD⁺ levels can be maintained by regeneration of NAD⁺ from nicotinamide via a salvage pathway or by de novo synthesis of NAD⁺ from tryptophan. Both pathways are conserved from yeast to humans. We describe a critical role of the NAD⁺-dependent deacetylase Hst1p as a sensor of NAD⁺ levels and regulator of NAD⁺ biosynthesis. Using transcript arrays, we show that low NAD⁺ states specifically induce the de novo NAD⁺ biosynthesis genes while the genes in the salvage pathway remain unaffected. The NAD⁺-dependent deacetylase activity of Hst1p represses de novo NAD⁺ biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect. The known Hst1p binding partner, Sum1p, is present at promoters of highly inducible NAD⁺ biosynthesis genes. The removal of HST1-mediated repression of the NAD⁺ de novo biosynthesis pathway leads to increased cellular NAD⁺ levels. Transcript array analysis shows that reduction in cellular NAD⁺ levels preferentially affects Hst1p-regulated genes in comparison to genes regulated with other NAD⁺-dependent deacetylases (Sir2p, Hst2p, Hst3p, and Hst4p). In vitro experiments demonstrate that Hst1p has relatively low affinity toward NAD⁺ in comparison to other NAD⁺-dependent enzymes. These findings suggest that Hst1p serves as a cellular NAD⁺ sensor that monitors and regulates cellular NAD⁺ levels.

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