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

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 aging phenotypes and cancer in both humans and mice. Reduced BubR1 expression is also a feature of chronological aging, but whether this age-related decline has biological consequences is unknown. Using a transgenic approach in mice, we show that sustained high 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 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.