151344 20251017144625.0 doi 10.1093/nar/gkab282 sideral 127134 ART-2021-127134 eng Silva-Pinheiro, P. DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion 2021 Access copy available to the general public Unrestricted Mutations in POLG, encoding POL¿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 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 POL¿, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POL¿B, the accessory subunit of the POL¿holoenzyme. This allows the free POL¿A to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POL¿A in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POL¿B acts to stabilize POL¿A and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POL¿subunits. We suggest that targeting POL¿A turnover can be exploited as a target for the development of future therapies. info:eu-repo/semantics/openAccess by-nc https://creativecommons.org/licenses/by-nc/4.0/deed.es 19.16 2021 BIOCHEMISTRY & MOLECULAR BIOLOGY 8 / 297 = 0.027 2021 Q1 T1 8.241 2021 Genetics 2021 Q1 28.0 2021 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Pardo-Hernández, C. Reyes, A. Tilokani, L. Mishra, A. Cerutti, R. Li, S. Rozsivalova, D.-H. Valenzuela, S. Dogan, S.A. Peter, B. Fernández-Silva, P. Universidad de Zaragoza (orcid)0000-0001-8971-7355 Trifunovic, A. Prudent, J. Minczuk, M. Bindoff, L. Macao, B. Zeviani, M. Falkenberg, M. Viscomi, C. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 49, 9 (2021), 5230-5248 Nucleic acids res. Nucleic Acids Research 0305-1048 9241319 http://zaguan.unizar.es/record/151344/files/texto_completo.pdf Versión publicada 3036288 http://zaguan.unizar.es/record/151344/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:151344 articulos driver 2025-10-17-14:23:51 ARTICLE