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

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...

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Autores principales: Henderson, David J.P., Miranda, JJ L., Emerson, Beverly M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630287/
https://www.ncbi.nlm.nih.gov/pubmed/29029387
http://dx.doi.org/10.18632/oncotarget.19841
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author Henderson, David J.P.
Miranda, JJ L.
Emerson, Beverly M.
author_facet Henderson, David J.P.
Miranda, JJ L.
Emerson, Beverly M.
author_sort Henderson, David J.P.
collection PubMed
description 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.
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spelling pubmed-56302872017-10-12 The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation Henderson, David J.P. Miranda, JJ L. Emerson, Beverly M. Oncotarget Priority Research Paper 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. Impact Journals LLC 2017-08-03 /pmc/articles/PMC5630287/ /pubmed/29029387 http://dx.doi.org/10.18632/oncotarget.19841 Text en Copyright: © 2017 Henderson et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Henderson, David J.P.
Miranda, JJ L.
Emerson, Beverly M.
The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation
title The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation
title_full The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation
title_fullStr The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation
title_full_unstemmed The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation
title_short The β-NAD(+) salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation
title_sort β-nad(+) salvage pathway and pkc-mediated signaling influence localized parp-1 activity and ctcf poly(adp)ribosylation
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630287/
https://www.ncbi.nlm.nih.gov/pubmed/29029387
http://dx.doi.org/10.18632/oncotarget.19841
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