Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy.
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 lower BUBR1 protein abundance. Low protein abundance is the direct result of the absence of transcripts from truncating mutants combined with high protein turnover of missense mutants. In this group of missense mutants, the amino acid change consistently occurs in or near the BUBR1 kinase domain. Our findings provide a molecular explanation for chromosomal instability in patients with biallelic genetic mutations in BUBR1.
Department of Physiological Chemistry and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, the Netherlands.
Saskia J E
SJ
Suijkerbuijk
Maria H J
MH
van Osch
Frank L
FL
Bos
Sandra
S
Hanks
Nazneen
N
Rahman
Geert J P L
GJ
Kops
D000015:Abnormalities, Multiple / Q000235:genetics*; D000782:Aneuploidy; D015152:Blotting, Northern; D020090:Chromosome Segregation / Q000235:genetics*; D005434:Flow Cytometry; D018816:Genes, cdc / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D008941:Spindle Apparatus / Q000473:pathology; D013577:Syndrome; D014162:Transfection; D014407:Tumor Cells, Cultured
C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases