Disease relevance of BUB3

• We found that the BUB gene family members including BUB1, BUBR1 and BUB3 are not frequent targets for mitotic checkpoint defects in lung cancers, if present at all [1].

High impact information on BUB3

• Bub3 null embryos appear normal up to day 3.5 pc but accumulate mitotic errors from days 4.5-6.5 pc in the form of micronuclei, chromatin bridging, lagging chromosomes, and irregular nuclear morphology [2].
• Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis [2].
• When the spindle checkpoint is activated at unattached kinetochores, the checkpoint proteins BubR1, Bub3 and Mad2 bind and inhibit Cdc20, an activator of the anaphase-promoting complex (APC) [3].
• Moreover, during mitosis, APC localizes to the ends of microtubules embedded in kinetochores and forms a complex with the checkpoint proteins Bub1 and Bub3 [4].
• Components of the spindle checkpoint include the mitotic arrest defective (MAD) genes MAD1-3, and the budding uninhibited by benzimidazole (BUB) genes BUB1 and BUB3 [5].

Biological context of BUB3

• BUB3 is a checkpoint gene that permits entry into mitosis depending upon the assembly state of microtubules [6].
• Transformation of mutant cells with genomic libraries repeatedly identified three different suppressors: the two wild-type alpha-tubulin genes, TUB1 and TUB3; and BUB3 [6].
• A 156-amino acid fragment of Bub1p functions in Bub3p binding and in kinetochore localization by one-hybrid assay [7].
• Retention of the BUB3 checkpoint protein on lagging chromosomes [8].
• Our findings demonstrate that GLEBS motifs reside in mammalian nucleoporins and mitotic checkpoint proteins and apparently serve as specific binding sites for either BUB3, RAE1, or both [9].

Anatomical context of BUB3

• Excess BUB3 rescues both the loss of viability and microtubule defects but not the benomyl supersensitivity associated with tub1-729 [6].
• The nocodazole-activated spindle checkpoint of HeLa cells was disrupted by expression of a 39 amino acid fragment (residues 382-420) of BubR1 containing the Bub3-binding GLEBS motif [10].

Associations of BUB3 with chemical compounds

• Intriguingly, the number of lagging chromosomes with high Bub3 staining increases dramatically in cells treated with low (and pharmacologically relevant) concentrations of the chemotherapeutic taxol and the microtubule poison nocodazole [8].

Physical interactions of BUB3

• Analysis of this activity indicates that the Bub3p-binding domain of Bub1p contributes to this phenotype through disruption of checkpoint activity as well as through introduction of kinetochore or spindle damage [7].

Enzymatic interactions of BUB3

• In vitro experiments confirmed that Bub1 possesses kinase activity; Bub1 was able to autophosphorylate and to catalyze phosphorylation of Bub3 [11].

Regulatory relationships of BUB3

• A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644 [12].

Other interactions of BUB3

• Two of the identified genes, BUB2 and BUB3, have been cloned and described (M. A. Hoyt, L. Totis, and B. T. Roberts, Cell 66:507-517, 1991) [11].
• Mutation of this motif abolishes checkpoint function, indicating that formation of the Mad1p-Bub1p-Bub3p complex is a crucial step in the spindle checkpoint mechanism [13].
• Comparison of the Bub3 sequence to the WD40 protein, Rae1, shows high sequence conservation along the same surfaces [14].
• Mad3 forms a stable heterodimer with Bub3 [15].

Analytical, diagnostic and therapeutic context of BUB3

• Genetic evidence was obtained suggesting that Bub1 and Bub3 are mutually dependent for function, and immunoprecipitation experiments demonstrated a physical association between the two [11].
• Sequence alignments indicate that these surfaces are mostly conserved across Bub3 proteins from diverse species [16].
• Molecular cloning and characterization of the human budding uninhibited by benomyl (BUB3) promoter [17].
• Negative-stain electron microscopy shows that Mad3 is an extended molecule ( approximately 200 A long), whereas Bub3 is globular [15].
• Assignment of BUB3 to human chromosome band 10q26 by in situ hybridization [18].

References