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Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan

Oncogene volume 32, pages 1193–1201 (2013)Cite this article

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Abstract

Mitochondrial dysfunction has been a hallmark of cancer. However, whether it has a causative role awaits to be elucidated. Here, using an animal model derived from inactivation of SUV3, a mitochondrial helicase, we demonstrated that mSuv3+/− mice harbored increased mitochondrial DNA (mtDNA) mutations and decreased mtDNA copy numbers, leading to tumor development in various sites and shortened lifespan. These phenotypes were transmitted maternally, indicating the etiological role of the mitochondria. Importantly, reduced SUV3 expression was observed in human breast tumor specimens compared with corresponding normal tissues in two independent cohorts. These results demonstrated for the first time that maintaining mtDNA integrity by SUV3 helicase is critical for cancer suppression.

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Acknowledgements

We thank Dennis Wang for his critical reading, Dr Tom Doetschman for providing 129/Sv mouse genomic library, Andrea Nikitin, Suna Cai and Weiwei Fan for their excellent assistance. This study was supported by grant NIH AG027877 to WHL and PLC, and NS21328 and AG13154 to DCW. Based on the UCI's policy, it is declared that WHL serves as a member of Board of Directors of GeneTex, Inc. This arrangement has been reviewed and approved by the UCI COI committee.

Author Contributions: PLC and WHL conceptualized experiments, prepared figures and drafted the manuscript. CFC performed majority of the experiments. YC performed the time pregnancy analysis. XEG performed cell experiments. JYS and CKH analyzed the SUV3 expression level in human tumor specimens and RLR analyzed histology experiments. DCW provided scientific advice and critical comments on manuscript.

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Authors and Affiliations

  1. Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA

    P-L Chen, C-F Chen, X E Guo & W-H Lee

  2. Department of Medicine, School of Medicine, University of California, Irvine, CA, USA

    Y Chen

  3. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    C-K Huang, J-Y Shew & W-H Lee

  4. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    R L Reddick

  5. Department of Biological Chemistry and Center for Molecular and Mitochondrial Medicine and Genetics, School of Medicine, University of California, Irvine, CA, USA

    D C Wallace

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  1. P-L Chen
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Chen, PL., Chen, CF., Chen, Y. et al. Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan. Oncogene 32, 1193–1201 (2013). https://doi.org/10.1038/onc.2012.120

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  • DOI: https://doi.org/10.1038/onc.2012.120

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