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Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease

Lookup NU author(s): Dr Thomas NichollsORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

MGME1, also known as Ddk1 or C20orf72, is a mitochondrial exonuclease found to be involved in the processing of mitochondrial DNA (mtDNA) during replication. Here, we present detailed insights on the role of MGME1 in mtDNA maintenance. Upon loss of MGME1, elongated 7S DNA species accumulate owing to incomplete processing of 5' ends. Moreover, an 11-kb linear mtDNA fragment spanning the entire major arc of the mitochondrial genome is generated. In contrast to control cells, where linear mtDNA molecules are detectable only after nuclease S1 treatment, the 11-kb fragment persists in MGME1-deficient cells. In parallel, we observed characteristic mtDNA duplications in the absence of MGME1. The fact that the breakpoints of these mtDNA rearrangements do not correspond to either classical deletions or the ends of the linear 11-kb fragment points to a role of MGME1 in processing mtDNA ends, possibly enabling their repair by homologous recombination. In agreement with its functional involvement in mtDNA maintenance, we show that MGME1 interacts with the mitochondrial replicase PolgA, suggesting that it is a constituent of the mitochondrial replisome, to which it provides an additional exonuclease activity. Thus, our results support the viewpoint that MGME1-mediated mtDNA processing is essential for faithful mitochondrial genome replication and might be required for intramolecular recombination of mtDNA.


Publication metadata

Author(s): Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2014

Volume: 23

Issue: 23

Pages: 6147-6162

Print publication date: 01/12/2014

Online publication date: 30/06/2014

Acceptance date: 25/06/2014

Date deposited: 14/05/2019

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddu336

DOI: 10.1093/hmg/ddu336

PubMed id: 24986917


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Funding

Funder referenceFunder name
0542/IP1/2011/71
279062
KU 911/21-1
MRC
ZS 99/3-1

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