Regulations of mitochondrial DNA repair by poly(ADP-Ribose) Polymerase 1

Formation of a repair enzyme complex is beneficial to DNA repair. Despite the fact that mitochondrial base excision repair (mtBER) enzymes DNA polymerase gamma (Pol {gamma}) and poly(ADP-ribose) polymerase 1 (PARP1) were found in the same complex, the functional role of the interaction in mtBER has not been characterized. We report studies that PARP1 regulates Pol {gamma} activity during DNA repair in a metabolic cofactor NAD+ (nicotinamide adenosine dinucleotide)-dependent manner. In the absence of NAD+, PARP1 completely inhibits Pol {gamma}, while increasing NAD+ level to physiological concentration enables Pol {gamma} to resume maximum repair activity. Pol {gamma} is PARylated when bound to DNA repair intermediates, and PARylation is essential for Pol {gamma} repair activity. The PARP1 inhibitor Olaparib that abolishes PARP1 catalytic activity suppresses Pol {gamma} gap-filling synthesis at physiological concentrations of NAD+, suggesting inhibiting PARP1 activity would increase mtDNA mutations. Because NAD+ cellular levels are linked to metabolism and to ATP production via oxidative phosphorylation, our results suggest that mtDNA damage repair is correlated with cellular metabolic state and integrity of the respiratory chain. Our results revealed a molecular basis of drug toxicity from prolonged usage of PARP1 inhibitors in treating cardiac dysfunctions