Regulation of poly(ADP-ribose) polymerase-1-dependent gene expression through promoter-directed recruitment of a nuclear NAD + synthase

Tong Zhang, Jhoanna G. Berrocal, Jie Yao, Michelle E. DuMond, Raga Krishnakumar, Donald D. Ruhl, Keun Woo Ryu, Matthew J. Gamble, W. Lee Kraus

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

NMNAT-1 and PARP-1, two key enzymes in the NAD + metabolic pathway, localize to the nucleus where integration of their enzymatic activities has the potential to control a variety of nuclear processes. Using a variety of biochemical, molecular, cell-based, and genomic assays, we show that NMNAT-1 and PARP-1 physically and functionally interact at target gene promoters in MCF-7 cells. Specifically, we show that PARP-1 recruits NMNAT-1 to promoters where it produces NAD + to support PARP-1 catalytic activity, but also enhances the enzymatic activity of PARP-1 independently of NAD + production. Furthermore, using two-photon excitation microscopy, we show that NMNAT-1 catalyzes the production of NAD + in a nuclear pool that may be distinct from other cellular compartments. In expression microarray experiments, depletion of NMNAT-1 or PARP-1 alters the expression of about 200 protein- coding genes each, with about 10% overlap between the two gene sets. NMNAT-1 enzymatic activity is required for PARP- 1-dependent poly(ADP-ribosyl)ation at the promoters of commonly regulated target genes, as well as the expression of those target genes. Collectively, our studies link the enzymatic activities of NMNAT-1 and PARP-1 to the regulation of a set of common target genes through functional interactions at target gene promoters.

Original languageEnglish (US)
Pages (from-to)12405-12416
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number15
DOIs
StatePublished - Apr 6 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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