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Lookup NU author(s): Dr Christin AlbusORCiD, Alejandro Rodriguez Luis, Dr Katja MengerORCiD, Dr Thomas NichollsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.
Author(s): Erdinc D, Albus CA, Rodriguez-Luis A, Menger KE, Thorsell A, Atanassov I, Rovsnik U, Falkenberg M, Gustafsson CM, Nicholls TJJ
Publication type: Article
Publication status: Published
Journal: Nucleic Acids Research
Year: 2025
Volume: 53
Issue: 20
Online publication date: 04/11/2025
Acceptance date: 29/09/2025
Date deposited: 02/04/2026
ISSN (electronic): 1362-4962
Publisher: Oxford University Press
URL: https://doi.org/10.1093/nar/gkaf1140
DOI: 10.1093/nar/gkaf1140
Data Access Statement: Proteomics data have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the PRIDE partner repository [ 47 ] with identifiers PXD063285 and PXD064926. Raw microscopy and blotting data have been uploaded to Zenodo and are available at https://doi.org/10.5281/zenodo.16872498
PubMed id: 41189053
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