| First Author | Silva-Pinheiro P | Year | 2021 |
| Journal | Nucleic Acids Res | Volume | 49 |
| Issue | 9 | Pages | 5230-5248 |
| PubMed ID | 33956154 | Mgi Jnum | J:307133 |
| Mgi Id | MGI:6712546 | Doi | 10.1093/nar/gkab282 |
| Citation | Silva-Pinheiro P, et al. (2021) DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion. Nucleic Acids Res 49(9):5230-5248 |
| abstractText | Mutations in POLG, encoding POLgammaA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLgamma, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLgammaB, the accessory subunit of the POLgamma holoenzyme. This allows the free POLgammaA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLgammaA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLgammaB acts to stabilize POLgammaA and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POLgamma subunits. We suggest that targeting POLgammaA turnover can be exploited as a target for the development of future therapies. |
