RT Journal Article
SR Electronic
T1 Poly(ADP-ribose) polymerase-1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.070110
DO 10.1124/mol.110.070110
A1 Andrea Lapucci
A1 Maria Pittelli
A1 Elena Rapizzi
A1 Roberta Felici
A1 Flavio Moroni
A1 Alberto Chiarugi
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/03/11/mol.110.070110.abstract
AB Poly(ADP-ribose)polymerase-1 (PARP-1) is a NAD-consuming enzyme with an emerging key role in epigenetic regulation of gene transcription. Although PARP-1 expression is classically restricted to the nucleus, a few studies report the mitochondrial localization of the enzyme and its ability to regulate organelle functioning. Here, we show that, in spite of exclusive nuclear localization of PARP-1, mitochondrial homeostasis is compromised in neuroblastoma cells exposed to PARP-1 pharmacological inhibitors or siRNA. PARP-1 suppression reduces integrity of mtDNA, as well as expression of mitochondria-encoded respiratory complex subunits COX-1, COX-2 and ND-2. Accordingly, PARP-1 localizes at promoters of nuclear genes encoding both the mtDNA repair proteins UNG1, MYH1 and APE1, and the mtDNA transcription factors TFB1M and TFB2M. Notably, poly(ADP-ribosyl)ation is required for nuclear gene expression of these mitochondrial proteins. Consistent with these findings, PARP-1 suppression impairs mitochondrial ATP production. Our results indicate that PARP-1 plays a central role in mitochondrial homeostasis by epigenetically regulating nuclear genes involved in mtDNA repair and transcription. Data might have important implications in pharmacology of PARP-1 inhibitors as well as clinical oncology and aging.