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

Nat Cell Biol. 2013 Jan;15(1):96-102. doi: 10.1038/ncb2643. Epub 2012 Dec 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Aging / metabolism*
  • Aging / pathology
  • Aneuploidy
  • Animals
  • Cell Count
  • Cell Cycle Proteins
  • Cells, Cultured
  • Chromosomal Instability
  • Female
  • Gene Expression*
  • Life Expectancy
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / metabolism*
  • Stem Cells / pathology

Substances

  • Bub1b protein, mouse
  • Cell Cycle Proteins
  • 9,10-Dimethyl-1,2-benzanthracene
  • BUB1 protein, human
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases