The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

S. A. Baechler, V. M. Factor, I. Dalla Rosa, A. Ravji, D. Becker, S. Khiati, L. M. Miller Jenkins, M. Lang, C. Sourbier, S. A. Michaels, L. M. Neckers, H. L. Zhang, A. Spinazzola, S. N. Huang, J. U. Marquardt and Y. Pommier ()
Additional contact information
S. A. Baechler: National Cancer Institute
V. M. Factor: National Cancer Institute
I. Dalla Rosa: University College London
A. Ravji: National Cancer Institute
D. Becker: Johannes Gutenberg University
S. Khiati: Universite d’Angers
L. M. Miller Jenkins: National Institutes of Health
M. Lang: National Institutes of Health
C. Sourbier: National Institutes of Health
S. A. Michaels: National Cancer Institute
L. M. Neckers: National Institutes of Health
H. L. Zhang: National Cancer Institute
A. Spinazzola: University College London
S. N. Huang: National Cancer Institute
J. U. Marquardt: Johannes Gutenberg University
Y. Pommier: National Cancer Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-07922-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07922-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-07922-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().