Alternative titles; symbols
HGNC Approved Gene Symbol: BUB3
Cytogenetic location: 10q26.13 Genomic coordinates (GRCh38) : 10:123,154,402-123,170,467 (from NCBI)
A feedback control mechanism, or cell cycle checkpoint, delays the onset of anaphase until all the chromosomes are correctly aligned on the mitotic spindle. Mutations in the S. cerevisiae BUB and MAD genes abolish this checkpoint, such that mutant cells fail to undergo mitotic arrest in response to spindle damage. The yeast BUB1 (see 602452) gene encodes a protein kinase that can bind and phosphorylate BUB3. Mammalian BUB1 localizes to the kinetochore of unaligned chromosomes. To further characterize the role of BUB1 in mitosis, Taylor et al. (1998) searched an EST database to identify the human homolog of BUB3. They identified a partial human BUB3 cDNA and used a PCR strategy to isolate a full-length cDNA. The predicted 328-amino acid human protein shares approximately 34% identity with yeast BUB3. Both proteins contain 4 WD repeats. When expressed in mammalian cells, a chimeric GFP-BUB3 protein localized to kinetochores before chromosome alignment. Using deletion analysis, the authors identified a domain of BUB1 that is required both for binding BUB3 and for kinetochore localization of BUB1. Taylor et al. (1998) reported that a similar domain in BUBR1 (602860) mediates binding to BUB3. They suggested that the BUB and MAD proteins may be part of a large protein complex that is recruited to unattached kinetochores and that dissociates from kinetochores upon achieving correct bipolar attachment.
By analysis of a radiation hybrid panel, Cahill et al. (1999) mapped the BUB3 gene to chromosome 10q24-q26.
De Voer et al. (2013) performed genomewide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer (CRC; see 114500), identifying haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 (602452) and BUB3 in 2.9%. In addition to CRC, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. De Voer et al. (2013) concluded that these results indicated that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age. De Voer et al. (2013) identified 3 individuals of European ancestry with heterozygous missense mutations in the BUB3 gene who presented with early-onset colon cancer at ages 29, 32, and 38 years. All had some family history of cancer; 2 had mosaic variegated aneuploidy, and 1 had dysmorphic features, including asymmetric face, crooked nose, and short philtrum. This last patient had had 16 pregnancies, including 13 spontaneous miscarriages, and had given birth to 3 healthy sons. She had a benign giant condyloma acuminatum at age 31, bilateral cataract at age 43, and lung carcinoma with multiple brain metastases at age 44. She had been smoking more than 20 cigarettes per day for over 20 years.
By gene-targeting techniques, Kalitsis et al. (2000) disrupted the Bub3 gene in mice, which resulted in embryonic lethality prior to day 8.5 postcoitum (pc) in homozygous mutants. Mutant embryos appeared normal at day 3.5 pc but rapidly degenerated. An observed accumulation of mitotic errors suggested that Bub3 is essential for normal mitosis and for early embryonic development in the mouse.
Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., Lengauer, C. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58: 181-187, 1999. [PubMed: 10366450] [Full Text: https://doi.org/10.1006/geno.1999.5831]
De Voer, R. M., Geurts Van Kessel, A., Weren, R. D. A., Ligtenberg, M. J. L., Smeets, D., Fu, L., Vreede, L., Kamping, E. J., Verwiel, E. T. P., Hahn, M.-M., Ariaans, M., Spruijt, L., and 9 others. Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology 145: 544-547, 2013. [PubMed: 23747338] [Full Text: https://doi.org/10.1053/j.gastro.2013.06.001]
Kalitsis, P., Earle, E., Fowler, K. J., Choo, K. H. A. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev. 14: 2277-2282, 2000. [PubMed: 10995385] [Full Text: https://doi.org/10.1101/gad.827500]
Taylor, S. S., Ha, E., McKeon, F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J. Cell Biol. 142: 1-11, 1998. [PubMed: 9660858] [Full Text: https://doi.org/10.1083/jcb.142.1.1]