DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion (vol 49, pg 5230, 2021)

Mutations in POLG, encoding POL gamma A, 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 Polg(A449T/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 POL gamma, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POL gamma B, the accessory subunit of the POL gamma holoenzyme. This allows the free POL gamma A to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POL gamma A in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POL gamma B acts to stabilize POL gamma A and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POL gamma subunits. We suggest that targeting POL gamma A turnover can be exploited as a target for the development of future therapies.[GRAPHICS].