Poly(ADP-ribose) polymerase 1 regulates mitochondrial DNA repair in an NAD-dependent manner
| Autor: | Geoffrey K. Herrmann, Nisha Jain Garg, William K. Russell, Y. Whitney Yin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
DNA Repair Protein Conformation DNA polymerase EMSA electrophoretic mobility shift assay Poly (ADP-Ribose) Polymerase-1 Biochemistry Poly ADP Ribosylation BME β-mercaptoethanol Protein Interaction Maps BER base excision repair FA formic acid hPARG human poly(ADP-Ribose) glycohydrolase biology Chemistry Editors' Pick Base excision repair DNA Polymerase gamma Cell biology DNA-Binding Proteins WB Western blot Mitochondrial DNA repair PARP1 Poly(ADP-Ribose) polymerase 1 ADP-ribosylation Pol γ mitochondrial DNA polymerase protein–DNA interaction TBST Tris-buffered saline supplemented with Tween-20 Research Article Mitochondrial DNA DNA repair Poly ADP ribose polymerase DNA Mitochondrial 03 medical and health sciences Humans Molecular Biology western blot DNA synthesis 030102 biochemistry & molecular biology Cell Biology ACN acetonitrile NAD mtDNA mitochondrial DNA Oxidative Stress protein–protein interaction 030104 developmental biology post-translational modification biology.protein NAD+ kinase Reactive Oxygen Species Protein Processing Post-Translational DNA Damage |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Mitochondrial DNA is located in organelle that house essential metabolic reactions and contains high reactive oxygen species. Therefore, mitochondrial DNA suffers more oxidative damage than its nuclear counterpart. Formation of a repair enzyme complex is beneficial to DNA repair. Recent studies have shown that mitochondrial DNA polymerase (Pol γ) and poly(ADP-ribose) polymerase 1 (PARP1) were found in the same complex along with other mitochondrial DNA repair enzymes, and mitochondrial PARP1 level is correlated with mtDNA integrity. However, the molecular basis for the functional connection between Pol γ and PARP1 has not yet been elucidated because cellular functions of PARP1 in DNA repair are intertwined with metabolism via NAD+ (nicotinamide adenosine dinucleotide), the substrate of PARP1, and a metabolic cofactor. To dissect the direct effect of PARP1 on mtDNA from the secondary perturbation of metabolism, we report here biochemical studies that recapitulated Pol γ PARylation observed in cells and showed that PARP1 regulates Pol γ activity during DNA repair in a metabolic cofactor NAD+ (nicotinamide adenosine dinucleotide)-dependent manner. In the absence of NAD+, PARP1 completely inhibits Pol γ, while increasing NAD+ levels to a physiological concentration that enables Pol γ to resume maximum repair activity. Because cellular NAD+ levels are linked to metabolism and to ATP production via oxidative phosphorylation, our results suggest that mtDNA damage repair is coupled to cellular metabolic state and the integrity of the respiratory chain. |
| Databáze: | OpenAIRE |
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