Cited by 78Mitochondrial Function and PathologyDNA Repair MechanismsAutophagy in Disease and Therapy

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

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Nicholls, Thomas J., Zsurka, Gábor, Peeva, Viktoriya, Schöler, Susanne, Szczesny, Roman J., Cysewski, Dominik, Reyes, Aurelio, Kornblum, Cornelia +5 more·2014·Human Molecular Genetics

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.

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Authors
Nicholls, T. J., Zsurka, G., Peeva, V., Schöler, S., Szczesny, R. J., Cysewski, D., Reyes, A., Kornblum, C., Sciacco, M., Moggio, M., Dziembowski, A., Kunz, W. S., & Minczuk, M.
Affiliations
  • MRC Mitochondrial Biology Unit (GB)
  • Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL)
  • University of Bonn (DE)
  • University of Milan (IT)
Corresponding author
  • Kunz, Wolfram S.
  • Minczuk, Michal
Venue
Human Molecular Genetics
Published
2014-06-30
Volume
23
Issue
23
Pages
6147-6162
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2103776029
Cited by
78
References
68
Citations by year
2026: 5 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 3 · 2020: 10 · 2019: 7 · 2018: 11 · 2017: 2 · 2016: 6 · 2015: 6
FWCI
1.91
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Human Molecular Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • European Commission (279062)
  • Deutsche Forschungsgemeinschaft (KU911/21-1, ZS 99/3-1)
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial DNA maintenance, mtDNA rearrangements, 5' end processing, homologous recombination, mitochondrial DNA replication, intramolecular recombination
MeSH terms
DNA Polymerase gamma, Cell Line, DNA-Directed DNA Polymerase, DNA Replication, DNA, Mitochondrial, Exodeoxyribonucleases, Humans, Mutation, Gene Rearrangement, Mitochondrial Diseases

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