Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Peeva, Viktoriya UNSPECIFIED UNSPECIFIED UNSPECIFIED Blei, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Trombly, Genevieve UNSPECIFIED UNSPECIFIED UNSPECIFIED Corsi, Sarah UNSPECIFIED orcid.org/0000-0002-8680-7870 UNSPECIFIED Szukszto, Maciej J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rebelo-Guiomar, Pedro UNSPECIFIED UNSPECIFIED UNSPECIFIED Gammage, Payam A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kudin, Alexei P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Minczuk, Michal UNSPECIFIED UNSPECIFIED UNSPECIFIED Zsurka, Gabor UNSPECIFIED orcid.org/0000-0002-6379-849X UNSPECIFIED Kunz, Wolfram S. UNSPECIFIED orcid.org/0000-0003-1113-3493 UNSPECIFIED
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:	Keywords Language POLYMERASE GAMMA; STRAND BREAKS; MUTATIONS; DELETIONS; ELIMINATION; REPAIR; ACCUMULATION; APOPTOSIS; GENOMES; SINGLE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18891