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Nat Commun. 2019 Jan 8;10(1):83. doi: 10.1038/s41467-018-07922-3.

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.

Author information

1
Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, NIH, National Cancer Institute, Bethesda, Maryland, 20892, USA.
2
Department of Clinical and Movement Neurosciences, Institute of Neurology, Royal Free Campus, University College London, London, NW3 2PF, UK.
3
Department of Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany.
4
Equipe MitoLab, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Universite d'Angers, 49933, Angers, France.
5
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
6
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MA, 20892, USA.
7
Laboratory of Molecular Oncology, Division of Biotechnology Review and Research I, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
8
Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, NIH, National Cancer Institute, Bethesda, Maryland, 20892, USA. pommier@nih.gov.

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.

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