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Poly(ADP-ribose) polymerase-1-induced NAD(+) depletion promotes nuclear factor-κB transcriptional activity by preventing p65 de-acetylation.

TitlePoly(ADP-ribose) polymerase-1-induced NAD(+) depletion promotes nuclear factor-κB transcriptional activity by preventing p65 de-acetylation.
Publication TypeJournal Article
Year of Publication2013
AuthorsKauppinen TM, Gan L, Swanson RA
JournalBiochim Biophys Acta
Date Published2013 Aug
KeywordsAcetylation, Animals, Astrocytes, Carbazoles, Cells, Cultured, eIF-2 Kinase, Humans, Methylnitronitrosoguanidine, Mice, NAD, NF-kappa B, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Sirtuin 1, Transcription, Genetic, Transcriptional Activation, Transfection

NF-κB is a transcription factor that integrates pro-inflammatory and pro-survival responses in diverse cell types. The activity of NF-κB is regulated in part by acetylation of its p65 subunit at lysine 310, which is required for transcription complex formation. De-acetylation at this site is performed by sirtuin 1(SIRT1) and possibly other sirtuins in an NAD(+) dependent manner, such that SIRT1 inhibition promotes NF-κB transcriptional activity. It is unknown, however, whether changes in NAD(+) levels can influence p65 acetylation and cellular inflammatory responses. Poly(ADP-ribose)-1 (PARP-1) is an abundant nuclear enzyme that consumes NAD(+) in the process of forming (ADP-ribose)polymers on target proteins, and extensive PARP-1 activation can reduce intracellular NAD(+) concentrations. Here we tested the idea that PARP-1 activation can regulate NF-κB transcriptional activity by reducing NAD(+) concentrations and thereby inhibiting de-acetylation of p65. Primary astrocyte cultures were treated with the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to induce PARP-1 activation. This resulted in sustained acetylation of p65 and increased NF-κB transcriptional activity as monitored by a κB-driven eGFP reporter gene. These effects of MNNG were negated by a PARP-1 inhibitor, in PARP-1(-/-) cells, and in PARP-1(-/-) cells transfected with a catalytically inactive PARP-1 construct, thus confirming that these effects are mediated by PARP-1 catalytic activity. The effects of PARP-1 activation were replicated by a SIRT1 inhibitor, EX-527, and were reversed by exogenous NAD(+). These findings demonstrate that PARP-1-induced changes in NAD(+) levels can modulate NF-κB transcriptional activity through effects on p65 acetylation.

Alternate JournalBiochim. Biophys. Acta
PubMed ID23597856
PubMed Central IDPMC4041949
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
R01 NS041421 / NS / NINDS NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 AG033017 / AG / NIA NIH HHS / United States