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

Silva-Pinheiro, P. (author)
Pardo-Hernandez, Carlos (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Reyes, A. (author)
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Tilokani, L. (author)
Mishra, Anup (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Cerutti, R. (author)
Li, S. F. (author)
Rozsivalova, D. H. (author)
Valenzuela, Sebastian, 1993 (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Dogan, S. A. (author)
Peter, Bradley (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Fernandez-Silva, P. (author)
Trifunovic, A. (author)
Prudent, J. (author)
Minczuk, M. (author)
Bindoff, L. (author)
Macao, Bertil, 1969 (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Zeviani, M. (author)
Falkenberg, Maria, 1968 (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Viscomi, C. (author)
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 (creator_code:org_t)
2021-05-06
2021
English.
In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 49:9, s. 5230-5248
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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] .

Subject headings

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Odontologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Dentistry (hsv//eng)

Keyword

human mitochondrial-DNA
accessory subunit
transcription factor
mtdna-maintenance
loop strands
lon protease
binding
replication
degradation
twinkle
Biochemistry & Molecular Biology

Publication and Content Type

ref (subject category)
art (subject category)

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