000151344 001__ 151344
000151344 005__ 20250307114715.0
000151344 0247_ $$2doi$$a10.1093/nar/gkab282
000151344 0248_ $$2sideral$$a127134
000151344 037__ $$aART-2021-127134
000151344 041__ $$aeng
000151344 100__ $$aSilva-Pinheiro, P.
000151344 245__ $$aDNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion
000151344 260__ $$c2021
000151344 5060_ $$aAccess copy available to the general public$$fUnrestricted
000151344 5203_ $$aMutations 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.
000151344 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/
000151344 590__ $$a19.16$$b2021
000151344 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b8 / 297 = 0.027$$c2021$$dQ1$$eT1
000151344 592__ $$a8.241$$b2021
000151344 593__ $$aGenetics$$c2021$$dQ1
000151344 594__ $$a28.0$$b2021
000151344 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000151344 700__ $$aPardo-Hernández, C.
000151344 700__ $$aReyes, A.
000151344 700__ $$aTilokani, L.
000151344 700__ $$aMishra, A.
000151344 700__ $$aCerutti, R.
000151344 700__ $$aLi, S.
000151344 700__ $$aRozsivalova, D.-H.
000151344 700__ $$aValenzuela, S.
000151344 700__ $$aDogan, S.A.
000151344 700__ $$aPeter, B.
000151344 700__ $$0(orcid)0000-0001-8971-7355$$aFernández-Silva, P.$$uUniversidad de Zaragoza
000151344 700__ $$aTrifunovic, A.
000151344 700__ $$aPrudent, J.
000151344 700__ $$aMinczuk, M.
000151344 700__ $$aBindoff, L.
000151344 700__ $$aMacao, B.
000151344 700__ $$aZeviani, M.
000151344 700__ $$aFalkenberg, M.
000151344 700__ $$aViscomi, C.
000151344 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000151344 773__ $$g49, 9 (2021), 5230-5248$$pNucleic acids res.$$tNucleic Acids Research$$x0305-1048
000151344 8564_ $$s9241319$$uhttps://zaguan.unizar.es/record/151344/files/texto_completo.pdf$$yVersión publicada
000151344 8564_ $$s3036288$$uhttps://zaguan.unizar.es/record/151344/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000151344 909CO $$ooai:zaguan.unizar.es:151344$$particulos$$pdriver
000151344 951__ $$a2025-03-07-09:32:41
000151344 980__ $$aARTICLE