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Two type I topoisomerases maintain DNA topology in human mitochondria

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.

Publication metadata

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


DOI: 10.1093/nar/gkac857


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Funder referenceFunder name
213464/Z/18/ZWellcome Trust
Wellcome Trust