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)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes.
Exportado de SIDERAL (2025-10-17-14:23:51)
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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)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. Exportado de SIDERAL (2025-10-17-14:23:51)
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Record created 2025-03-07, last modified 2025-10-17