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

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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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Poly(ADP-ribose) Polymerases
Gene expression
Genes
Gene Expression
NAD
MCF-7 Cells
Metabolic Networks and Pathways
Photons
Adenosine Diphosphate
Microarrays
NAD+ synthase
Poly (ADP-Ribose) Polymerase-1
Microscopy
Catalyst supports
Assays
Catalyst activity
Microscopic examination
Enzymes
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Regulation of poly(ADP-ribose) polymerase-1-dependent gene expression through promoter-directed recruitment of a nuclear NAD + synthase. / Zhang, Tong; Berrocal, Jhoanna G.; Yao, Jie; DuMond, Michelle E.; Krishnakumar, Raga; Ruhl, Donald D.; Ryu, Keun Woo; Gamble, Matthew J.; Kraus, W. Lee.

In: Journal of Biological Chemistry, Vol. 287, No. 15, 06.04.2012, p. 12405-12416.

Research output: Contribution to journalArticle

Zhang, Tong ; Berrocal, Jhoanna G. ; Yao, Jie ; DuMond, Michelle E. ; Krishnakumar, Raga ; Ruhl, Donald D. ; Ryu, Keun Woo ; Gamble, Matthew J. ; Kraus, W. Lee. / Regulation of poly(ADP-ribose) polymerase-1-dependent gene expression through promoter-directed recruitment of a nuclear NAD + synthase. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 15. pp. 12405-12416.
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