Silva-Pinheiro, Pedro ORCID: 0000-0002-0872-5749, Pardo-Hernandez, Carlos, Reyes, Aurelio ORCID: 0000-0003-2876-2202, Tilokani, Lisa, Mishra, Anup, Cerutti, Raffaele, Li, Shuaifeng, Rozsivalova, Dieu-Hien, Valenzuela, Sebastian ORCID: 0000-0001-5153-8431, Dogan, Sukru A., Peter, Bradley, Fernandez-Silva, Patricio, Trifunovic, Aleksandra, Prudent, Julien, Minczuk, Michal ORCID: 0000-0001-8242-1420, Bindoff, Laurence, Macao, Bertil, Zeviani, Massimo ORCID: 0000-0002-9067-5508, Falkenberg, Maria and Viscomi, Carlo ORCID: 0000-0001-6050-0566 (2021). DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion. Nucleic Acids Res., 49 (9). S. 5230 - 5249. OXFORD: OXFORD UNIV PRESS. ISSN 1362-4962

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Abstract

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] .

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Silva-Pinheiro, PedroUNSPECIFIEDorcid.org/0000-0002-0872-5749UNSPECIFIED
Pardo-Hernandez, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reyes, AurelioUNSPECIFIEDorcid.org/0000-0003-2876-2202UNSPECIFIED
Tilokani, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mishra, AnupUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cerutti, RaffaeleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, ShuaifengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rozsivalova, Dieu-HienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valenzuela, SebastianUNSPECIFIEDorcid.org/0000-0001-5153-8431UNSPECIFIED
Dogan, Sukru A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peter, BradleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Silva, PatricioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prudent, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Minczuk, MichalUNSPECIFIEDorcid.org/0000-0001-8242-1420UNSPECIFIED
Bindoff, LaurenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Macao, BertilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeviani, MassimoUNSPECIFIEDorcid.org/0000-0002-9067-5508UNSPECIFIED
Falkenberg, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viscomi, CarloUNSPECIFIEDorcid.org/0000-0001-6050-0566UNSPECIFIED
URN: urn:nbn:de:hbz:38-600406
DOI: 10.1093/nar/gkab282
Journal or Publication Title: Nucleic Acids Res.
Volume: 49
Number: 9
Page Range: S. 5230 - 5249
Date: 2021
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1362-4962
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HUMAN MITOCHONDRIAL-DNA; ACCESSORY SUBUNIT; TRANSCRIPTION FACTOR; MTDNA-MAINTENANCE; LOOP STRANDS; LON PROTEASE; BINDING; REPLICATION; DEGRADATION; TWINKLEMultiple languages
Biochemistry & Molecular BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60040

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