Abstract
Like any genome, mitochondrial DNA (mtDNA) also requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases. The last years have brought a closer insight into the function of these fascinating enzymes in mtDNA topology regulation, replication, transcription, and segregation. Here, we summarize the current knowledge about mitochondrial topoisomerases, paying special attention to mammalian mitochondrial genome maintenance. We also discuss the open gaps in the existing knowledge of mtDNA topology control and the potential involvement of mitochondrial topoisomerases in human pathologies. While Top1mt, the only exclusively mitochondrial topoisomerase in mammals, has been studied intensively for nearly a decade, only recent studies have shed some light onto the mitochondrial function of Top2β and Top3α, enzymes that are shared between nucleus and mitochondria. Top3α mediates the segregation of freshly replicated mtDNA molecules, and its dysfunction leads to mtDNA aggregation and copy number depletion in patients. Top2β, in contrast, regulates mitochondrial DNA replication and transcription through the alteration of mtDNA topology, a fact that should be acknowledged due to the frequent use of Topoisomerase 2 inhibitors in medical therapy.
Highlights
Like any genome, mitochondrial DNA requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases
Top2β was found to be actively recruited to DNA double-strand breaks (DSB) in nuclear DNA, and its knockout impaired their repair by homologous recombination [17], indicating that this topoisomerase has an additional function in DNA repair
We found that high doses of the fluoroquinolone ciprofloxacin do inhibit mitochondrial Top2β, leading to the accumulation of supercoiled mitochondrial DNA (mtDNA) and impaired mtDNA replication [38]
Summary
All organisms require DNA topoisomerases to resolve sterical problems during the maintenance and expression of their genomes. Two sub-groups of Type I topoisomerases are known—Type IA enzymes open the strand by binding to the 5 -end of the cut site and allow a second strand to pass through They can decatenate single-stranded DNA and relax negative supercoils. Type IB enzymes catalyze single strand break-mediated relaxation, they are not structurally related to Type 1A enzymes and alter DNA topology by rotation instead of strand passage These enzymes can relax both positive and negative supercoils and bind to the 3 -end of the cut DNA. In ring-shaped genomes, replication can lead to the formation of hemicatenanes, where the strands are connected by a single-strand interlock, requiring a type I topoisomerase for resolution Besides their various functions in DNA replication, topoisomerases participate in homologous recombination of DNA. Top2β was found to be actively recruited to DNA double-strand breaks (DSB) in nuclear DNA, and its knockout impaired their repair by homologous recombination [17], indicating that this topoisomerase has an additional function in DNA repair
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