| First Author | Bakthavatchalu V | Year | 2012 |
| Journal | Oncogene | Volume | 31 |
| Issue | 17 | Pages | 2129-39 |
| PubMed ID | 21909133 | Mgi Jnum | J:190273 |
| Mgi Id | MGI:5448514 | Doi | 10.1038/onc.2011.407 |
| Citation | Bakthavatchalu V, et al. (2012) Manganese superoxide dismutase is a mitochondrial fidelity protein that protects Polgamma against UV-induced inactivation. Oncogene 31(17):2129-39 |
| abstractText | Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusively in the mitochondrial matrix. Genotoxic agents, such as ultraviolet (UV) radiation, generates oxidative stress and cause mitochondrial DNA (mtDNA) damage. The mtDNA polymerase (Polgamma), a major constituent of nucleoids, is responsible for the replication and repair of the mitochondrial genome. Recent studies suggest that the mitochondria contain fidelity proteins and MnSOD constitutes an integral part of the nucleoid complex. However, it is not known whether or how MnSOD participates in the mitochondrial repair processes. Using skin tissue from C57BL/6 mice exposed to UVB radiation, we demonstrate that MnSOD has a critical role in preventing mtDNA damage by protecting the function of Polgamma. Quantitative-PCR analysis shows an increase in mtDNA damage after UVB exposure. Immunofluorescence and immunoblotting studies demonstrate p53 translocation to the mitochondria and interaction with Polgamma after UVB exposure. The mtDNA immunoprecipitation assay with Polgamma and p53 antibodies in p53(+/+) and p53(-/-) mice demonstrates an interaction between MnSOD, p53 and Polgamma. The results suggest that these proteins form a complex for the repair of UVB-associated mtDNA damage. The data also demonstrate that UVB exposure injures the mtDNA D-loop in a p53-dependent manner. Using MnSOD-deficient mice we demonstrate that UVB-induced mtDNA damage is MnSOD dependent. Exposure to UVB results in nitration and inactivation of Polgamma, which is prevented by addition of the MnSOD mimetic Mn(III)TE-2-PyP(5+). These results demonstrate for the first time that MnSOD is a fidelity protein that maintains the activity of Polgamma by preventing UVB-induced nitration and inactivation of Polgamma. The data also demonstrate that MnSOD has a role along with p53 to prevent mtDNA damage. |
