The entire BUB3 gene is approximately 16.2 Kb (start: 123154277 and end: 123170467 bp; orientation: Forward strand).

The BUB3 gene encodes for 4 transcript variants: there are two transcript variants deposited in the NCBI database (https://www.ncbi.nlm.nih.gov/gene) and two additional transcript variants reported in Ensembl (http://www.ensembl.org/). The transcript variant 1 is the longest transcript variant (exons: 8, coding exons: 7, transcript length: 7828 bp) and encodes the isoform a (328 amino acids [aa]). The transcript variant 2 present an alternative splice site in 3 coding region (exons: 8, coding exons: 7, transcript length: 1361 bp), which leads to a frameshift and a shorter and distinct C-terminus compared to isoform a (isoform b, 326 aa). The transcript variant 3 present 6 coding exons, a transcript length of 895 bp and a translation length of 278 aa. The transcript variant 4 is shorter transcript presenting 5 exons (being 4 coding exons), a transcript length 667 bp and resulting protein of 145 aa.

BUB3 is a WD40 protein that create a symmetric circular wall around a central pore or funnel region with its seven-blade β-propeller structure, acting as a scaffolding protein for its binding partners BUB1B (BUBR1) and BUB1 (Prinz et al., 2016; Seeley et al., 1999). The primary structure of BUB3 is illustrated in Figure 1.

Ubiquitous.

BUB3 is localized preferentially in unattached kinetochores during mitosis (especially prometaphase), participating of mitotic checkpoint complex (Sudakin et al., 2001). In interphase cells, BUB3 is localized in cytosol (Yoon et al., 2004).

BUB3 protein is a component of the mitotic checkpoint complex (MCC), which present a crucial activity monitoring the state of chromosome attachment to the mitotic (or meiotic) fuse and prevents loss of sister chromatid cohesion and premature chromosome segregation in the presence of unattached or incorrectly attached chromosomes to the spindle by inhibition of the anaphase-promoting complex/cyclosome (APC/C) (Lopes et al., 2005; Musacchio, 2015). The canonical BUB3-related cellular signaling is illustrated in Figure 2.
Using a Drosophila melanogaster model, Morais da Silva and colleagues (Morais da Silva et al., 2013) reported that BUB3 inhibition resulted in increased proliferative potential, promoted tumorigenesis and widespread chromosomal aneuploidy. Interesting, loss of cytoplasmatic, but not attached-kinetochore, BUB3 pool was found to be driven tumorigenesis, indicating a novel non-kinetochore-dependent tumor suppressing function for BUB3 (Morais da Silva et al., 2013). Additional non-canonical functions of BUB3 had been described during interphase. BUB3 and CDC20 form a complex with histone deacetylases, which seems to confer transcriptional repressor activity (Yoon et al., 2004). Wan and colleagues (Wan et al., 2015) reported that BUB3 regulates RNA splicing, R-loop formation, DNA damage, and TP53 activation.

The BUB3 gene and protein is highly homologous among different species, as shown in Table 1.
Table 1. Comparative identity of human BUB3 with other species.

% Identity for: Homo sapiens BUB3	Symbol	Protein	DNA
vs. P.troglodytes	BUB3	100.0	99.8
vs. M.mulatta	BUB3	100.0	98.8
vs. B.taurus	BUB3	100.0	93.5
vs. M.musculus	Bub3	100.0	90.4
vs. R.norvegicus	Bub3	100.0	91.1
vs. G.gallus	BUB3	96.9	84.0
vs. X.tropicalis	bub3	93.2	79.5
vs. D.rerio	bub3	86.2	73.7
vs. D.melanogaster	Bub3	61.1	59.9
vs. A.gambiae	AgaP_AGAP010544	62.0	59.2
vs. S.pombe	bub3	38.0	45.0
vs. A.thaliana	BUB3.1	55.1	55.0
vs. A.thaliana	BUB3.2	56.3	55.8
vs. O.sativa	Os03g0448600	56.3	57.4

(Source: http://www.ncbi.nlm.nih.gov/homologene)

Recurrent mutations in the BUB3 gene are rare. A total of 81 unique samples presented BUB3 mutations, which are distributed on 75 different mutations (60 missense substitutions, 10 synonymous substitutions, 1 nonsense substitutions, 2 inframe deletions and 2 frameshift deletions), were found among the 47120 unique samples reported in COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic). In agreement, 0.2% of 74247 tested samples presented BUB3 somatic mutation as reported in cBioPortal (http://www.cbioportal.org), which correspond to 154 mutations: 132 missense substitutions, 17 truncating and 5 inframe mutations. Of note, there are 55 duplicate mutations in patients with multiple samples. A total of 472 (0.8 %) samples presented any type of genetic alteration in BUB3, when mutations, amplifications, deep deletions and multiple alterations were considered in 55817 cancer samples. These findings corroborate initial studies in different types of cancer (Hernando et al., 2001).