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

Darren J Baker, Meelad M. Dawlaty, Tobias Wijshake, Karthik B. Jeganathan, Liviu Malureanu, Janine H. Van Ree, Ruben Crespo-Diaz, Santiago Reyes, Lauren Seaburg, Virginia M Shapiro, Atta Behfar, Andre Terzic, Bart Van De Sluis, Jan Van Deursen

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143 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)96-102
Number of pages7
JournalNature Cell Biology
Volume15
Issue number1
DOIs
StatePublished - Jan 2013

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M Phase Cell Cycle Checkpoints
Kinetochores
Aneuploidy
Microtubules
Premature Aging
Chromosomal Instability
Chromosome Segregation
Germ-Line Mutation
Neoplasms
Carcinogenesis
Phenotype
Genes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. / Baker, Darren J; Dawlaty, Meelad M.; Wijshake, Tobias; Jeganathan, Karthik B.; Malureanu, Liviu; Van Ree, Janine H.; Crespo-Diaz, Ruben; Reyes, Santiago; Seaburg, Lauren; Shapiro, Virginia M; Behfar, Atta; Terzic, Andre; Van De Sluis, Bart; Van Deursen, Jan.

In: Nature Cell Biology, Vol. 15, No. 1, 01.2013, p. 96-102.

Research output: Contribution to journalArticle

Baker, DJ, Dawlaty, MM, Wijshake, T, Jeganathan, KB, Malureanu, L, Van Ree, JH, Crespo-Diaz, R, Reyes, S, Seaburg, L, Shapiro, VM, Behfar, A, Terzic, A, Van De Sluis, B & Van Deursen, J 2013, 'Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan', Nature Cell Biology, vol. 15, no. 1, pp. 96-102. https://doi.org/10.1038/ncb2643
Baker, Darren J ; Dawlaty, Meelad M. ; Wijshake, Tobias ; Jeganathan, Karthik B. ; Malureanu, Liviu ; Van Ree, Janine H. ; Crespo-Diaz, Ruben ; Reyes, Santiago ; Seaburg, Lauren ; Shapiro, Virginia M ; Behfar, Atta ; Terzic, Andre ; Van De Sluis, Bart ; Van Deursen, Jan. / Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. In: Nature Cell Biology. 2013 ; Vol. 15, No. 1. pp. 96-102.
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