The β-NAD+ salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP) ribosylation

David J.P. Henderson, J. J.L. Miranda, Beverly Emerson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Poly(ADP)ribosylation (PARylation) of the chromatin architectural protein CTCF is critical for CTCF-dependent regulation of chromatin boundary and insulator elements. Loss of CTCF PARylation results in epigenetic silencing of certain tumor suppressor genes through destabilization of nearby chromatin boundaries. We investigated the metabolic and mechanistic processes that regulate PARP-1-mediated CTCF PARylation in human cancer cell lines and discovered a key role for the expression and activity of β-NAD+ salvage enzymes, NAMPT and NMNAT-1. These enzymes are downregulated in cells that exhibit reduced CTCF PARylation, resulting in a decreased concentration of nuclear β-NAD+. In these cells, decreased NMNAT-1 expression is enforced by a proteasome-mediated feedback loop resulting in degradation of NMNAT-1, transcriptional repression of NAMPT, and suppression of PARP-1 activity. Interestingly, dePARylated CTCF is associated in a stable protein complex with PARP-1 and NMNAT-1 in cancer cells harboring silenced tumor suppressor genes. Although the metabolic context in these cells favors suppression of PARP-1 activity, CTCF PARylation can be restored by Protein Kinase C (PKC) signaling. PKC induces dissociation of the catalytically inactive PARP-1/NMNAT-1/CTCF protein complex and phosphorylation of NMNAT-1, which stimulates its proteasome-mediated degradation. Our findings suggest that CTCF PARylation is underpinned by a cellular metabolic context engendered by regulation of the β-NAD+ salvage pathway in which NMNAT-1 acts as a rheostat to control localized β-NAD+ synthesis at CTCF/PARP-1 complexes.

Original languageEnglish (US)
Pages (from-to)64698-64713
Number of pages16
JournalOncotarget
Volume8
Issue number39
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

NAD
Adenosine Diphosphate
Protein Kinase C
Insulator Elements
Chromatin
Proteasome Endopeptidase Complex
Tumor Suppressor Genes
Enzymes
Epigenomics
Neoplasms
Down-Regulation
Phosphorylation
Cell Line
Proteins
CCCTC-binding factor

Keywords

  • CTCF
  • NMNAT-1
  • PARP-1
  • Poly(ADP)ribosylation
  • β-NAD

ASJC Scopus subject areas

  • Oncology

Cite this

The β-NAD+ salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP) ribosylation. / Henderson, David J.P.; Miranda, J. J.L.; Emerson, Beverly.

In: Oncotarget, Vol. 8, No. 39, 01.01.2017, p. 64698-64713.

Research output: Contribution to journalArticle

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