DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion

Silva-Pinheiro, P. ; 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) ; Trifunovic, A. ; Prudent, J. ; Minczuk, M. ; Bindoff, L. ; Macao, B. ; Zeviani, M. ; Falkenberg, M. ; Viscomi, C.

Resumen: 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.

Idioma: Inglés

DOI: 10.1093/nar/gkab282

Año: 2021

Publicado en: Nucleic Acids Research 49, 9 (2021), 5230-5248
ISSN: 0305-1048

Factor impacto JCR: 19.16 (2021)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 8 / 297 = 0.027 (2021) - Q1 - T1

Factor impacto CITESCORE: 28.0 - Biochemistry, Genetics and Molecular Biology (Q1)

Factor impacto SCIMAGO: 8.241 - Genetics (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)