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.

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

“…High‐level expression of BubR1 extends mice lifespan and delays age‐related deterioration and aneuploidy (Baker et al., 2013). Similarly, a marked reduction of BubR1 levels was detected in oocytes from old women and aged mice (Lagirand‐Cantaloube et al., 2017; Pan, Ma, Zhu, & Schultz, 2008; Riris et al., 2014).…”

“…Through SAC signal activation, BubR1 participates in proper chromosome segregation during mitosis (Baker et al., 2013; Lampson & Kapoor, 2005). BubR1, is required at several key steps in oocyte meiosis, and more specifically, for SAC activity, the timing of the first meiotic division, and the stable attachment of chromosomes to the spindle (Brunet, Pahlavan, Taylor, & Maro, 2003; Wei et al., 2010).…”

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

“…Aneuploidy, defined as a number of chromosomes different from an integer multiple of the haploid complement, is another phenomenon that correlates with an organism's age: The prevalence of aneuploidy increases in both somatic and germline tissues as organisms age (Lushnikova et al ., 2011; Nagaoka et al ., 2012; Baker et al ., 2013). While it is often proposed that the correlation between age and aneuploidy is due to increased rates of chromosomal missegregation in older cells, it is possible that the relationship is more complex and that aneuploidy itself contributes to aging phenotypes.…”

“…Aneuploidy is further connected to aging by work in mice studying the effects of somatic aneuploidy on aging phenotypes. Mice have delayed aging phenotypes in tissues where the age‐associated rate of aneuploidy is also delayed (Baker et al ., 2013). Conversely, mice with high levels of somatic aneuploidy due to mutations in the mitotic checkpoint protein BubR1 have decreased lifespans and premature aging phenotypes, while overexpression of BubR1 in mice decreases age‐associated somatic aneuploidy and extends lifespan (Baker et al ., 2004, 2013).…”

“…Mice have delayed aging phenotypes in tissues where the age‐associated rate of aneuploidy is also delayed (Baker et al ., 2013). Conversely, mice with high levels of somatic aneuploidy due to mutations in the mitotic checkpoint protein BubR1 have decreased lifespans and premature aging phenotypes, while overexpression of BubR1 in mice decreases age‐associated somatic aneuploidy and extends lifespan (Baker et al ., 2004, 2013). The human homolog of BubRI, BUB1B , is mutated in a rare human disorder known as mosaic variegated aneuploidy (MVA) syndrome (Matsuura et al ., 2006); although individuals with this syndrome have limited life expectancies, they also have elevated rates of cancer and multiple congenital anomalies, making any assessment of an accelerated aging phenotype very difficult.…”