Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters

Tong Zhang, Jhoanna G. Berrocal, Kristine M. Frizzell, Matthew J. Gamble, Michelle E. DuMond, Raga Krishnakumar, Tianle Yang, Anthony A. Sauve, W. Lee Kraus

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) constitute a nuclear NAD+ salvage pathway which regulates the functions of NAD+-dependent enzymes such as the protein deacetylase SIRT1. One of the major functions of SIRT1 is to regulate target gene transcription through modification of chromatin-associated proteins. However, little is known about the molecular mechanisms by which NAD+ biosynthetic enzymes regulate SIRT1 activity to control gene transcription in the nucleus. In this study we show that stable short hairpin RNA-mediated knockdown of NAMPT or NMNAT-1 in MCF-7 breast cancer cells reduces total cellular NAD+ levels and alters global patterns of gene expression. Furthermore, we show that SIRT1 plays a key role in mediating the gene regulatory effects of NAMPT and NMNAT-1. Specifically, we found that SIRT1 binds to the promoters of genes commonly regulated by NAMPT, NMNAT-1, and SIRT1 and that SIRT1 histone deacetylase activity is regulated by NAMPT and NMNAT-1 at these promoters. Most significantly, NMNAT-1 interacts with, and is recruited to target gene promoters by SIRT1. Collectively, our results reveal a mechanism for the direct control of SIRT1 deacetylase activity at a set of target gene promoters by NMNAT-1. This mechanism, in collaboration with NAMPT-dependent regulation of nuclear NAD+ production, establishes an important pathway for transcription regulation by NAD+.

Original languageEnglish (US)
Pages (from-to)20408-20417
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number30
DOIs
StatePublished - Jul 24 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhang, T., Berrocal, J. G., Frizzell, K. M., Gamble, M. J., DuMond, M. E., Krishnakumar, R., Yang, T., Sauve, A. A., & Lee Kraus, W. (2009). Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters. Journal of Biological Chemistry, 284(30), 20408-20417. https://doi.org/10.1074/jbc.M109.016469