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Lookup NU author(s): Dr Katja MengerORCiD, Dr James ChapmanORCiD, Mushtaq Khazeem, Dr Dasha Deen, John CasementORCiD, Valeria Di Leo, Dr Angela Pyle, Alejandro Rodriguez Luis, Dr Ian CowellORCiD, Professor Caroline AustinORCiD, Dr Thomas NichollsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Genetic processes require the activity of multiple topoisomerases, essential enzymes that remove topological tension and intermolecular linkages in DNA. We have investigated the subcellular localisation and activity of the six human topoisomerases with a view to understanding the topological maintenance of human mitochondrial DNA. Our results indicate that mitochondria contain two topoisomerases, TOP1MT and TOP3A. Using molecular, genomic and biochemical methods we find that both proteins contribute to mtDNA replication, in addition to the decatenation role of TOP3A, and that TOP1MT is stimulated by mtSSB. Loss of TOP3A or TOP1MT also dysregulates mitochondrial gene expression, and both proteins promote transcription elongation in vitro. We find no evidence for TOP2 localisation to mitochondria, and TOP2B knockout does not affect mtDNA maintenance or expression. Our results suggest a division of labour between TOP3A and TOP1MT in mtDNA topology control that is required for the proper maintenance and expression of human mtDNA.
Author(s): Menger KE, Chapman J, Díaz-Maldonado H, Khazeem MM, Deen D, Erdinc D, Casement JW, Di Leo V, Pyle A, Rodríguez-Luis A, Cowell IG, Falkenberg M, Austin CA, Nicholls TJ
Publication type: Article
Publication status: Published
Journal: Nucleic Acids Research
Year: 2022
Online publication date: 10/10/2022
Acceptance date: 26/09/2022
Date deposited: 11/10/2022
ISSN (print): 0305-1048
ISSN (electronic): 1362-4962
Publisher: Oxford University Press
URL: https://doi.org/10.1093/nar/gkac857
DOI: 10.1093/nar/gkac857
Data Access Statement: https://doi.org/10.5281/zenodo.7115828
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