Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA

Nicholls, Thomas J.; Nadalutti, Cristina A.; Motori, Elisa; Sommerville, Ewen W.; Gorman, Gráinne; Basu, Swaraj; Hoberg, Eike; Turnbull, Doug M.; Chinnery, Patrick F.; Larsson, Nils-Göran; Larsson, Erik; Falkenberg, Maria; Taylor, Robert W.; Griffith, Jack D.; Gustafsson, Claes M.

doi:10.1016/j.molcel.2017.11.033

Cited by 99 publications

(159 citation statements)

References 48 publications

(59 reference statements)

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“…Here, we suggest that the replication of H-strand is terminated with the DNA nick sealing before the completion of L-strand replication and this should generates hemicatenanes (two intertwined circular DNA associated through a ss linkage) (Figure 3, step 4), rather than catenanes (two intertwined circular DNA associated through a ds linkage). In agreement with our hypothetical model, recently it has been demonstrated that the mtDNA replication termination occurs via a hemicatenane formed at the O H site and that TopoIIIα is essential for resolving this structure (Nicholls et al 2018). It should be noted that in the past, Laurie and colleagues proposed a similar mechanism of the generation of hemicatenanes through alternative replication termination of circular DNA molecules (Laurie et al 1998).…”

Section: A Hypothesis On the Origin Of Mtdna Mutationssupporting

confidence: 86%

“…MtSSB binds to ssDNA and stimulates the activity of PolG (Farr et al 1999;Korhonen et al 2004). In addition to the above mentioned proteins, mitochondrial genome maintenance exonuclease 1 (MGME1) (Kornblum et al 2013), DNA ligase IIIα (Lakshmipathy and Campbell 1999;Puebla-Osorio et al 2006), Ribonuclease H1 (RNase H1) (Cerritelli et al 2003;Holmes et al 2015), DNA helicase/nuclease 2 (DNA2) , DNA flapstructure endonuclease 1 (FEN1) (Kalifa et al 2009) and mitochondrial isoform of Topoisomerase IIIα (TopoIIIα) (Nicholls et al 2018) are required for mtDNA maintenance and replication.…”

Section: Replication Of Mtdnamentioning

confidence: 99%

“…Intriguingly, the mtDNA replication termination results in the formation of a hemicatenane, two-ring interlocked DNA molecules at the O H site via ssDNA linkage. Recently, it has been demonstrated that the decatenation of mtDNA after replication termination is catalyzed by TopoIIIα, which is essential for the segregation of nucleoids within the mitochondria (Nicholls et al 2018). The mtDNA hemicatenane is unusual in the context of segregation of replicated circular double-stranded (ds)DNA molecules because this process in general proceeds via catenanes, DNA rings mechanically-interlocked via dsDNA linkage.…”

Section: Replication Of Mtdnamentioning

confidence: 99%

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DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Matkarimov

Saparbaev

2019

Preprint

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A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T→C/G→A transitions preferentially occur on the Light strand, whereas C→T/A→G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membrane via D-loop structure.

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Section: A Hypothesis On the Origin Of Mtdna Mutationssupporting

confidence: 86%

Section: Replication Of Mtdnamentioning

confidence: 99%

Section: Replication Of Mtdnamentioning

confidence: 99%

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DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Matkarimov

Saparbaev

2019

Preprint

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“…Some of the patients described above that harbor TOP3A mutations display severe cardiomyopathy reminiscent of that seen in disorders associated with mitochondrial abnormalities (113). Furthermore, a compound heterozygous mutation of TOP3A has been identified in an individual with a mitochondrial disorder (157). Significantly, the only functional protein expressed in this case carried an amino acid substitution in the TOP3A core catalytic domain (M100V).…”

Section: Roles Of Mitochondrial Top3amentioning

confidence: 93%

The many lives of type IA topoisomerases

Bizard

Hickson

2020

Journal of Biological Chemistry

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The double helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and compaction. However, these design advantages come at the cost of having to evolve and maintain a cellular machinery that can manipulate a long polymeric molecule that readily becomes topologically entangled whenever it has to open for translation, replication, or repair. If such a machinery fails to eliminate detrimental topological entanglements, utilization of the information stored in the DNA double helix is compromised. As a consequence, the use of Bform DNA as the carrier of genetic information must have co-evolved with a means to manipulate its complex topology. This duty is performed by DNA topoisomerases, which therefore are, unsurprisingly, ubiquitous in all kingdoms of life. In this review, we focus on how DNA topoisomerases catalyze their impressive range of DNA-conjuring tricks, with a particular emphasis on DNA topoisomerase III (TOP3). Once thought to be the most unremarkable of topoisomerases, the many lives of these type IA topoisomerases are now being progressively revealed. This research interest is driven by a realization that their substrate versatility and their ability to engage in intimate collaborations with translocases and other DNA-processing enzymes are far more extensive and impressive than was thought hitherto. This, coupled with the recent associations of TOP3s with developmental and neurological pathologies in humans, is clearly making us reconsider their undeserved reputation as being unexceptional enzymes.

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“…We implemented a custom-variant filtering strategy that anticipated either a dominant or recessive aetiology, prioritising rare or novel variants in nuclear genes encoding DNA replisome machinery or mitochondrial-localised proteins. 37 Figure 1F). Analysis of copy number variants (CNVs) identified by WES did not disclose rearrangements encompassing GMPR.…”

Section: Case Reportmentioning

confidence: 97%

Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late‐onset disorder of mitochondrial DNA maintenance

et al. 2019

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Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions.Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine

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Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA

Cited by 99 publications

References 48 publications

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

The many lives of type IA topoisomerases

Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late‐onset disorder of mitochondrial DNA maintenance

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