Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition

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127 Citations (Scopus)

Abstract

Sir2 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase involved in gene silencing and longevity. Cellular stresses affect Sir2 activity, but the mechanisms of Sir2 regulation are debated. Nicotinamide has been proposed as a physiological regulator that inhibits Sir2 deacetylase activity by chemical reversal of a covalent reaction intermediate. We demonstrate a chemical strategy to activate Sir2-dependent transcriptional silencing and present evidence that the endogenous level of nicotinamide limits Sir2 activity in wild-type (wt) yeast cells. Nicotinamide inhibition of Sir2 is antagonized in vitro by isonicotinamide, which causes an increase in Sir2 deacetylation activity. Isonicotinamide also substantially increases transcriptional silencing at Sir2-regulated loci in wt strains and in strains lacking key NAD+ salvage pathway enzymes (PNC1 and NPT1). Thus, a nicotinamide antagonist is a Sir2 agonist in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)595-601
Number of pages7
JournalMolecular Cell
Volume17
Issue number4
DOIs
StatePublished - Feb 18 2005

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Niacinamide
NAD
Gene Silencing
Yeasts
Enzymes
Proteins
In Vitro Techniques
isonicotinamide

ASJC Scopus subject areas

  • Molecular Biology

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Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition. / Sauve, Anthony A.; Moir, Robyn D.; Schramm, Vern L.; Willis, Ian M.

In: Molecular Cell, Vol. 17, No. 4, 18.02.2005, p. 595-601.

Research output: Contribution to journalArticle

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