title: Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease.
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.
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge, UK.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nicholls
authors.affiliation: Department of Epileptology, Life and Brain Center and.
authors.forename: Gábor
authors.initials: G
authors.lastname: Zsurka
authors.affiliation: Department of Epileptology, Life and Brain Center and.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Peeva
authors.affiliation: Department of Epileptology, Life and Brain Center and.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schöler
authors.affiliation: Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland and.
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Szczesny
authors.affiliation: Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Cysewski
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge, UK.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Department of Neurology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kornblum
authors.affiliation: Neuromuscular Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Sciacco
authors.affiliation: Neuromuscular Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.affiliation: Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland and.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dziembowski
authors.affiliation: Department of Epileptology, Life and Brain Center and michal.minczuk@mrc-mbu.cam.ac.uk wolfram.kunz@ukb.uni-bonn.de.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge, UK, michal.minczuk@mrc-mbu.cam.ac.uk wolfram.kunz@ukb.uni-bonn.de.
authors.forename: Michal
authors.initials: M
authors.lastname: Minczuk
mesh_terms: D002460:Cell Line; D000074002:DNA Polymerase gamma; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D015321:Gene Rearrangement; D006801:Humans; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D009154:Mutation
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D005090:Exodeoxyribonucleases; C579164:MGME1 protein, human