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

Author:

Silva-Pinheiro Pedro1ORCID,Pardo-Hernández Carlos2ORCID,Reyes Aurelio1ORCID,Tilokani Lisa1,Mishra Anup2,Cerutti Raffaele3,Li Shuaifeng4,Rozsivalova Dieu-Hien5,Valenzuela Sebastian2ORCID,Dogan Sukru A6,Peter Bradley2,Fernández-Silva Patricio7ORCID,Trifunovic Aleksandra5ORCID,Prudent Julien1,Minczuk Michal1,Bindoff Laurence89,Macao Bertil2ORCID,Zeviani Massimo310,Falkenberg Maria2ORCID,Viscomi Carlo11

Affiliation:

1. MRC/University of Cambridge Mitochondrial Biology Unit, Hills Road, CB2 0XY Cambridge, UK

2. Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Medicinaregatan 9A P.O. Box 440, SE405 30 Gothenburg, Sweden

3. Department of Neurosciences, University of Padova, via Giustiniani, 2-35128 Padova, Italy

4. Center for Cancer Biology, Life Science of Institution, Zhejiang University, Hangzhou 310058, China

5. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany

6. Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogazici University, 34342 Istanbul, Turkey

7. Biochemistry and Molecular and Cell Biology Department, University of Zaragoza, C/ Pedro Cerbuna s/n 50.009-Zaragoza, and Biocomputation and Complex Systems Physics Institute (BIFI), C/ Mariano Esquillor, 50.018-Zaragoza, Spain

8. Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway

9. Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway

10. Venetian Institute of Molecular Medicine, via Orus 2-35128 Padova, Italy

11. Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B-35131 Padova, Italy

Abstract

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

Funder

Telethon Foundation

Fondation NRJ pour les Neurosciences - Institute de France Grant

Associazione Luigi Comini Onlus

Medical Research Council

Marie Sklodowska-Curie ITN-REMIX

Swedish Research Council

Swedish Cancer Foundation

European Research Council

Knut and Alice Wallenberg Foundation

MRC Graduate Student Fellowship

EMBO Installation Grant

Bogazici University

Publisher

Oxford University Press (OUP)

Subject

Genetics

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