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Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan

Nature Cell Biology volume 15, pages 96–102 (2013)Cite this article

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Abstract

The BubR1 gene encodes for a mitotic regulator that ensures accurate segregation of chromosomes through its role in the mitotic checkpoint and the establishment of proper microtubule–kinetochore attachments. Germline mutations that reduce BubR1 abundance cause aneuploidy, shorten lifespan and induce premature ageing phenotypes and cancer in both humans and mice. A reduced BubR1 expression level is also a feature of chronological ageing, but whether this age-related decline has biological consequences is unknown. Using a transgenic approach in mice, we show that sustained high-level expression of BubR1 preserves genomic integrity and reduces tumorigenesis, even in the presence of genetic alterations that strongly promote aneuplodization and cancer, such as oncogenic Ras. We find that BubR1 overabundance exerts its protective effect by correcting mitotic checkpoint impairment and microtubule–kinetochore attachment defects. Furthermore, sustained high-level expression of BubR1 extends lifespan and delays age-related deterioration and aneuploidy in several tissues. Collectively, these data uncover a generalized function for BubR1 in counteracting defects that cause whole-chromosome instability and suggest that modulating BubR1 provides a unique opportunity to extend healthy lifespan.

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Figure 1: Transgenic mouse strains with moderate and high levels of Flag–BubR1 are chromosomally stable.
Figure 2: Resistance to tumorigenesis and chromosomal instability in BubR1 transgenic mice.
Figure 3: Increased BubR1 expression protects against spontaneous tumours and extends lifespan.
Figure 4: Increased BubR1 expression delays select age-related pathologies.

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Acknowledgements

We thank P. Galardy, R. Ricke, J. Kirkland, N. LeBrasseur and R. Miller for feedback on the manuscript, and K. Nath and J. Grande for help with the analysis of kidney phenotypes. This study was supported by NIH grants CA96985 and AG41122, the Ellison Medical Foundation, the Noaber Foundation and The Kogod Center on Aging.

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  1. Darren J. Baker and Meelad M. Dawlaty: Joint first authors

Authors and Affiliations

  1. Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA

    Darren J. Baker, Tobias Wijshake, Karthik B. Jeganathan, Liviu Malureanu, Janine H. van Ree & Jan M. van Deursen

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA

    Darren J. Baker, Meelad M. Dawlaty, Liviu Malureanu & Jan M. van Deursen

  3. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands

    Tobias Wijshake & Bart van de Sluis

  4. Department of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA

    Ruben Crespo-Diaz, Santiago Reyes, Atta Behfar & Andre Terzic

  5. Department of Immunology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA

    Lauren Seaburg & Virginia Shapiro

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Contributions

D.J.B., M.M.D., T.W., K.B.J., L.M., J.H.v.R., R.C.D., S.R., A.B., A.T., L.S., V.S. and J.M.v.D.designed and performed experiments, B.v.d.S. helped supervise T.W., and D.J.B. and J.M.v.D. wrote the manuscript. All authors discussed results, prepared figures and edited the manuscript.

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Correspondence to Jan M. van Deursen.

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Baker, D., Dawlaty, M., Wijshake, T. et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15, 96–102 (2013). https://doi.org/10.1038/ncb2643

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