Linear mitochondrial DNA is rapidly degraded by components of the replication machinery.

TitleLinear mitochondrial DNA is rapidly degraded by components of the replication machinery.
Publication TypeJournal Article
Year of Publication2018
AuthorsPeeva, V, Blei, D, Trombly, G, Corsi, S, Szukszto, MJ, Rebelo-Guiomar, P, Gammage, PA, Kudin, AP, Becker, C, Altmüller, J, Minczuk, MA, Zsurka, G, Kunz, WS
JournalNat Commun
Volume9
Issue1
Pagination1727
Date Published2018 Apr 30
ISSN2041-1723
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.

DOI10.1038/s41467-018-04131-w
Alternate JournalNat Commun
Citation Key10.1038/s41467-018-04131-w
PubMed ID29712893
PubMed Central IDPMC5928156