Peeva, Viktoriya, Blei, Daniel, Trombly, Genevieve, Corsi, Sarah ORCID: 0000-0002-8680-7870, Szukszto, Maciej J., Rebelo-Guiomar, Pedro, Gammage, Payam A., Kudin, Alexei P., Becker, Christian, Altmueller, Janine, Minczuk, Michal, Zsurka, Gabor ORCID: 0000-0002-6379-849X and Kunz, Wolfram S. ORCID: 0000-0003-1113-3493 (2018). Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. Nat. Commun., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5'-3' exonuclease MGME1, elimination of the 3'-5' exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Peeva, ViktoriyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blei, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trombly, GenevieveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corsi, SarahUNSPECIFIEDorcid.org/0000-0002-8680-7870UNSPECIFIED
Szukszto, Maciej J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rebelo-Guiomar, PedroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gammage, Payam A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kudin, Alexei P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Minczuk, MichalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zsurka, GaborUNSPECIFIEDorcid.org/0000-0002-6379-849XUNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDorcid.org/0000-0003-1113-3493UNSPECIFIED
URN: urn:nbn:de:hbz:38-188913
DOI: 10.1038/s41467-018-04131-w
Journal or Publication Title: Nat. Commun.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
POLYMERASE GAMMA; STRAND BREAKS; MUTATIONS; DELETIONS; ELIMINATION; REPAIR; ACCUMULATION; APOPTOSIS; GENOMES; SINGLEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18891

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