Molecular Causes for BUBR1 Dysfunction in the Human Cancer Predisposition Syndrome Mosaic Variegated Aneuploidy
Abstract via OpenAlex
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.
Evidence snapshot note
This reference is cited by the validated MVA · BUB1B evidence snapshot (data as of 2026-10-17) as Suijkerbuijk et al. — molecular causes of BUBR1 dysfunction.
- Model in the source
- U2OS/HeLa BUBR1 depletion and replacement
- Where in the publication
- Figures 4D and 5; comparator variants, not N1002K
- Cited by evidence records
- MVA-N1002K-GATE-002, MVA-L737-NMD-FIRST-001
The note describes how the snapshot used the source; it is not a summary of the publication's conclusions.
Identifiers and provenance
- DOI
10.1158/0008-5472.can-09-4319- PMID
20516114- PMCID
PMC2887387- Metadata from
- Crossref, Europe PMC, OpenAlex, fetched
- Open access
- Not flagged
- Added
- from the MVA evidence snapshot
In the library
- Collections
- MVA Hackathon 2026 — BUB1B
- Tags
- None yet
- Keywords from the source
- BubR1, spindle assembly checkpoint, biallelic variants, missense mutations, truncating mutations, chromosome segregation errors, chromosomal instability, protein turnover, microtubule attachment, cancer predisposition syndromes