Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy.

ABSTRACT: Genetic mutations in the mitotic regulatory kinase BUBR1 are associated with the cancer-susceptible disorder mosaic variegated aneuploidy (MVA). In patients with biallelic mutations, a missense mutation pairs with a truncating mutation. Here, we show that cell lines derived from MVA patients with biallelic mutations have an impaired mitotic checkpoint, chromosome alignment defects, and low overall BUBR1 abundance. Ectopic expression of BUBR1 restored mitotic checkpoint activity, proving that BUBR1 dysfunction causes chromosome segregation errors in the patients. Combined analysis of patient cells and functional protein replacement shows that all MVA mutations fall in two distinct classes: those that impose specific defects in checkpoint activity or microtubule attachment and those that low

SUBMITTER: Suijkerbuijk SJ 

PROVIDER: S-EPMC2887387 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature