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eNeuro. 2017 Aug 18;4(4). pii: ENEURO.0089-17.2017. doi: 10.1523/ENEURO.0089-17.2017. eCollection 2017 Jul-Aug.

Poly (ADP-Ribose) Polymerase-1 (PARP-1) Induction by Cocaine Is Post-Transcriptionally Regulated by miR-125b.

Author information

1
Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208.
2
Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville, TN 37208.
3
School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208.
4
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208.
5
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232.
6
Department of Microbiology and Immunology, Meharry Medical College, Nashville, TN 37208.
7
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

Abstract

Cocaine exposure alters gene expression in the brain via methylation and acetylation of histones along with methylation of DNA. Recently, poly (ADP-ribose) polymerase-1 (PARP-1) catalyzed PARylation has been reported as an important regulator of cocaine-mediated gene expression. In this study, we report that the cellular microRNA "miR-125b" plays a key role for cocaine-induced PARP-1 expression. Acute and chronic cocaine exposure resulted in the downregulation of miR-125b concurrent with upregulation of PARP-1 in dopaminergic neuronal cells and nucleus accumbens (NAc) of mice but not in the medial prefrontal cortex (PFC) or ventral tegmental area (VTA). In silico analysis predicted a binding site of miR-125b in a conserved 3'-untranslated region (3'UTR) of the PARP-1 mRNA. Knockdown and overexpression studies showed that miR-125b levels negatively correlate with PARP-1 protein expression. Luciferase reporter assay using a vector containing the 3'UTR of PARP-1 mRNA confirmed regulation of PARP-1 by miR-125b. Specific nucleotide mutations within the binding site abrogated miR-125b's regulatory effect on PARP-1 3'UTR. Finally, we established that downregulation of miR-125b and concurrent upregulation of PARP-1 is dependent on binding of cocaine to the dopamine transporter (DAT). Collectively, these results identify miR-125b as a post-transcriptional regulator of PARP-1 expression and establish a novel mechanism underlying the molecular effects of cocaine action.

KEYWORDS:

PARP-1; PARylation; cocaine; miRNA; post-transcriptional regulation

PMID:
28828398
PMCID:
PMC5562297
DOI:
10.1523/ENEURO.0089-17.2017
[Indexed for MEDLINE]
Free PMC Article

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