BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))

2011-07-01   Victor M Bolanos-Garcia , Tom L Blundell 

Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK

Identity

HGNC
LOCATION
2q13
LOCUSID
ALIAS
BUB1A,BUB1L,hBUB1
FUSION GENES

DNA/RNA

Atlas Image
Figure 1. Schematic representation of the human bub1 gene demonstrating the relative size of each of the 25 exons (introns are not drawn to scale).
Atlas Image

Description

The gene spans 40.2 kb and is composed of 25 exons.

Transcription

NM_004336.3, see pdf above.

Proteins

Note

Uniprot accession number: NP_004327.1.
ENZYME entry (serine/threonine protein kinase): EC 2.7.11.1.
Amino acid sequence (FASTA format): see pdf above.
Atlas Image
Figure 2. Domain organization of BUB1. Three main regions can be identified in the BUB1 gene product: a conserved N-terminal region, which contains the kinetochore localization domain; an intermediate, non-conserved region, which is required for Bub3 binding; and a C-terminal region containing a catalytic serine/threonine kinase domain. The main functions associated with the different BUB1 regions are also indicated.

Description

1085 amino acids, 122.37 kDa.

Expression

Ubiquituously expressed.

Localisation

Cytoplasmic in interphase cells. It is localized in nuclear kinetochores in cells with an unsatisfied mitotic checkpoint in a process that requires BUB1 binding to Blinkin and BUB3.

Function

BUB1 is required for chromosome congression, kinetochore localization of BUBR1, CENP-E, CENP-F and Mad2 in cells with mitotic checkpoint unsatisfied and for the establishment and/or maintenance of efficient bipolar attachment to spindle microtubules (Johnson et al., 2004; Lampson and Kapoor, 2005; McGuinness et al., 2009). Deletion of Bub1 from S. pombe increases the rate of chromosome missegregation (Bernard et al., 1998) while deletion of Bub1 from S. cerevisiae results in slow growth and elevated chromosome loss (Warren et al., 2002).
BUB1 is recruited very early in prophase (Wong and Fang, 2006) and is essential for assembly of the functional inner centromere (Taylor et al., 1998; Boyarchuk et al., 2007). It accumulates at the kinetochore in SAC-activated cells and assures the correct kinetochore formation.
The N-terminal region mediates the binding of BUB1 to the mitotic kinetochore protein Blinkin (a protein also commonly referred to as KNL1/Spc105/AF15q14); the interaction is essential for the kinetochore localization of BUB1 induced in cells with an unsatisfied mitotic checkpoint (Kiyomitsu et al., 2007). N-terminal BUB1 is organised as a triple tandem of the TPR motif (Bolanos-Garcia et al., 2009). In fission yeast, the Bub1 N-terminal residues 1-179 are required for targeting the protein Shugoshin 1 (SGO1) to centromeres (Vaur et al., 2005) while deletion of residues 28-160 results in a truncated protein unable to recruit Bub3 and Mad3/BUB1B to kinetochores (Vanoosthuyse et al., 2004). The C-terminal region contains a catalytic, serine threonine kinase domain that resembles the mechanism of activation of CDKs by cyclins (Kang et al., 2008).

Homology

The bub1 gene is conserved in chimpanzee, cow, mouse, rat, chicken, and zebrafish. Homology exists with the gene encoding for the mitotic checkpoint kinase BUBR1 (a BUB1 paralogue) (Bolanos-Garcia and Blundell, 2011).

Mutations

Note

Bub1 region MutationResidueDomainClinical conditionReference
N-terminalGAG→GATE36→DTPR domain Colorectal cancerCahill et al., 1999
DeletionΔ76-141, frameshiftColorectal cancerCahill et al., 1998
GCT→TCTA130→SLymph node metastasisShichiri et al., 2002
G→A140, transition of the splicing donor siteColorectal cancerCahill et al., 1998
GLEBS motifCGA→CAAR209→QLung cancerSato et al., 2000
GGT→GATG250→NATLLOhshima et al., 2000*
TAT→TGTY259→CPancreatic cancerHempen et al., 2003
CAC→AACH265→NPancreatic cancerHempen et al., 2003
Middle region of low structural complexity TCC→TTCS375→FColorectal cancerSaeki et al., 2002
TCT→TATS492→YColorectal cancerCahill et al., 1998
AAG→AGGK566→RColorectal cancerSaeki et al., 2002
CCC→CGCP648→RColorectal cancerCahill et al., 1999
C-terminalDeletionΔ827, frameshiftTyroid follicular adenomaOuyang et al., 2002
S950→GKinase domainColorectal cancerImai et al., 1999

Table 1. Human bub1 mutations associated with cancer. *These authors incorrectly number these residues; the numbering shown here is the correct.

The following somatic mutations have been reported to date: A130->S (Shichiri et al., 2002); deletion delta76-141 (Cahill et al., 1998); 140, transition of the splicing donor site (Cahill et al., 1998); S492->Y (Cahill et al., 1998); deletion delta827 (Ouyang et al., 2002); G250->N (Ohshima et al., 2000); S950->G (Imai et al., 1999); Y259->C (Hempen et al., 2003); H265->N (Hempen et al., 2003). It could not be determined whether the R209->Q substitution was the result of a somatic mutation or due to a rare polymorphism because constitutional DNA from the patient harbouring this mutation was not available (Sato et al., 2000). The clinical condition associated to each mutation is described in Table 1. The mapping of residues substitutions onto the BUB1 domains is depicted in Figure 3.

Atlas Image
Figure 3. Mapping of cancer associated substitutions onto the amino acid sequence of human BUB1.

Implicated in

Entity name
Colorectal cancer
Disease
Colorectal cancer, also referred to as bowel cancer, is characterized by neoplasia in the colon, rectum, or vermiform appendix. Colorectal cancer is the third most commonly diagnosed cancer in the world and fourth most frequent cause of cancer death in males. More than half of the people who die of colorectal cancer live in a developed region of the world.
Cytogenetics
RT-PCR mediated amplification and direct sequencing of the entire BUB1 coding region in the colorectal cancer cell line V400 revealed an internal deletion of 197 bp of this gene (Cahill et al., 1998). The deletion results in the remotion of codons 76 to 141 and creates a frameshift immediately thereafter. Sequence analysis of cDNA from another colorectal cancer cell line, V429, revealed a missense mutation at codon 492 that resulted in the substitution of tyrosine for a conserved serine (Cahill et al., 1998). The V400 and V429 mutations were heterozygous, somatic and present in primary tumours but not in normal tissues. Another heterozygous BUB1 missense mutation (AGT to GGT) at codon 950 has been identified (Imai et al., 1999).
Entity name
Hepatocellular carcinoma (HCC)
Disease
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide and it accounts for most liver cancers. HCC occurs more often in men than women and is more common in people ages 30-50. Hepatitis virus infection, alcohol consumption, and dietary exposure to toxins such as aflatoxin B1 are associated with the occurrence of HCC.
Cytogenetics
Two BUB1 gene variants have been identified in HCC specimens (Saeki et al., 2002). The expression product of one variant has a serine (TCC) substituted for phenylalanine (TTC) at codon 375 while the other has a lysine (AAG) substituted for arginine (AGG) at codon 566 (Saeki et al., 2002). S375F showed a well-differentiated HCC in cirrhotic liver caused by hepatitis B virus, whereas K566R showed a moderately differentiated HCC in hepatitis C virus induced cirrhotic liver. Genomic DNA extracted from nontumorous liver tissue revealed the same variants in both cases.
Entity name
Lung cancer
Disease
Lung cancer is the most frequently diagnosed cancer among men. The mortality rate is the highest among men and the second highest among women worldwide. The main types of lung cancer are small-cell lung carcinoma and non-small-cell lung carcinoma. Non-small-cell lung carcinoma is sometimes treated with surgery, while small-cell lung carcinoma usually responds better to chemotherapy and radiation. Lung cancer cells harbour many cytogenetic abnormalities suggestive of allele loss, including non-reciprocal translocations and aneuploidy. The stage of the disease is a strong predictor of survival, suggesting that early detection is needed for improvement in treatment outcomes.
Cytogenetics
A nucleotide change of the BUB1 gene that results in the substitution of Arginine by Glutamine R209Q has been identified in the cell line NCI-H345 (Sato et al., 2000). Unfortunately, it was not possible to determine whether the change was a somatic mutation or a rare polymorphism because constitutional DNA from this patient was not available.
Entity name
Adult T-cell leukaemia/lymphoma (ATLL)
Disease
Lymphomas, malignancies of the lymphoid cells, are divided on the basis of their pathologic features into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Adult T-cell leukemia/lymphoma (ATLL) is usually a highly aggressive non-Hodgkins lymphoma of the patients own T-cells with no characteristic histologic appearance except for a diffuse pattern and a mature T-cell phenotype. The frequent isolation of HTLV-1 from patients with this disease and the detection of HTLV-1 proviral genome in ATLL leukemic cells suggest that HTLV-1 causes ATLL.
Cytogenetics
A BUB1 missense mutation of G to A at codon 250 (GGT to GAT) has been reported (Ohshima et al., 2000).
Entity name
Pancreatic cancer
Disease
The term pancreatic cancer usually refers to adenocarcinoma that arises within the exocrine component of the pancreas. Pancreatic cancer is one of the most aggressive diseases with most cancers and often has a poor prognosis: for all stages combined, the 1- and 5-year relative survival rates are 25% and 6%, respectively; for local disease the 5-year survival is approximately 20% while the median survival for locally advanced and for metastatic disease, which collectively represent over 80% of individuals, is about 10 and 6 months respectively.
Cytogenetics
Two missense variants in the BUB1 gene have been identified in the aneuploid pancreatic cell line Hs766T (Hempen et al., 2003). These mutations are found in the same allele, accompanied by a wild-type BUB1 allele. Mutation of nucleotide 776 from an adenine to a guanine results in an amino acid change at codon 259 from tyrosine to cysteine (Y259C). A second mutation at nucleotide 793 changed a cytosine to an adenine (C to A) thus resulting in the mutant H265N (Hempen et al., 2003).
Entity name
Thyroid follicular adenoma
Disease
Almost all thyroid adenomas are follicular adenomas. Follicular adenomas can be described as "cold", "warm" or "hot" depending on their level of function. Histopathologically, follicular adenomas can be classified according to their cellular architecture and relative amounts of cellularity and colloid into the following types:
- fetal (microfollicular), which have the potential for microinvasion,
- colloid (macrofollicular), which do not have any potential for microinvasion,
- embryonal (atypical), which have the potential for microinvasion.
Cytogenetics
A thyroid follicular carcinoma that has a 2-bp somatic deletion (G2480/A2481) of BUB1 has been reported by Ouyang and collaborators (2002).
Entity name
Lymph node metastasis
Disease
Certain cancers spread in a predictable fashion from where the cancer started. Because the flow of lymph is directional, if the cancer spreads it will spread first to lymph nodes close to the tumor before it spreads to other parts of the body.
Cytogenetics
A BUB1 missense somatic mutation (nucleotide 437 GCT to TCT transition) that replaces Ala to Ser at codon 130 has been identified in an ascending colorectal carcinoma (Shichiri et al., 2002).

Bibliography

Pubmed IDLast YearTitleAuthors
98643541998Fission yeast bub1 is a mitotic centromere protein essential for the spindle checkpoint and the preservation of correct ploidy through mitosis.Bernard P et al
208887752011BUB1 and BUBR1: multifaceted kinases of the cell cycle.Bolanos-Garcia VM et al
173892282007Bub1 is essential for assembly of the functional inner centromere.Boyarchuk Y et al
95213271998Mutations of mitotic checkpoint genes in human cancers.Cahill DP et al
103664501999Characterization of MAD2B and other mitotic spindle checkpoint genes.Cahill DP et al
126555612003A double missense variation of the BUB1 gene and a defective mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T.Hempen PM et al
105432551999Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers.Imai Y et al
150206842004Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression.Johnson VL et al
189958372008Structure and substrate recruitment of the human spindle checkpoint kinase Bub1.Kang J et al
179811352007Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1.Kiyomitsu T et al
155924592005The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.Lampson MA et al
192492082009Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint.McGuinness BE et al
109607632000Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma.Ohshima K et al
119400462002Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1.Ouyang B et al
119329082002Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma.Saeki A et al
108354952000Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer.Sato M et al
117823502002Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival.Shichiri M et al
91827601997Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage.Taylor SS et al
155097832004Kinetochore targeting of fission yeast Mad and Bub proteins is essential for spindle checkpoint function but not for all chromosome segregation roles of Bub1p.Vanoosthuyse V et al
163606882005Control of Shugoshin function during fission-yeast meiosis.Vaur S et al
122211132002Distinct chromosome segregation roles for spindle checkpoint proteins.Warren CD et al
179984002007Cdk1 phosphorylation of BubR1 controls spindle checkpoint arrest and Plk1-mediated formation of the 3F3/2 epitope.Wong OK et al

Other Information

Locus ID:

NCBI: 699
MIM: 602452
HGNC: 1148
Ensembl: ENSG00000169679

Variants:

dbSNP: 699
ClinVar: 699
TCGA: ENSG00000169679
COSMIC: BUB1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000169679ENST00000302759O43683
ENSG00000169679ENST00000409311O43683
ENSG00000169679ENST00000420328C9JRC7
ENSG00000169679ENST00000436916C9IYH4
ENSG00000169679ENST00000447014C9JQA4
ENSG00000169679ENST00000535254O43683
ENSG00000169679ENST00000666956A0A590UK50
ENSG00000169679ENST00000671097A0A590UJ99

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
Progesterone-mediated oocyte maturationKEGGko04914
Cell cycleKEGGhsa04110
Progesterone-mediated oocyte maturationKEGGhsa04914
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases Activate ForminsREACTOMER-HSA-5663220
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
M PhaseREACTOMER-HSA-68886
Mitotic PrometaphaseREACTOMER-HSA-68877
Resolution of Sister Chromatid CohesionREACTOMER-HSA-2500257
Mitotic Metaphase and AnaphaseREACTOMER-HSA-2555396
Mitotic AnaphaseREACTOMER-HSA-68882
Separation of Sister ChromatidsREACTOMER-HSA-2467813

References

Pubmed IDYearTitleCitations
159313892005Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer.297
209297752010Two histone marks establish the inner centromere and chromosome bi-orientation.185
156041522004Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis.99
157237972005Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization.97
159337232005A dual role for Bub1 in the spindle checkpoint and chromosome congression.96
117928042001Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells.88
194874562009Bub1 regulates chromosome segregation in a kinetochore-independent manner.82
216464032011Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation.67
167604282006Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1.61
189228732009Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding.59

Citation

Victor M Bolanos-Garcia ; Tom L Blundell

BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))

Atlas Genet Cytogenet Oncol Haematol. 2011-07-01

Online version: http://atlasgeneticsoncology.org/gene/853/bub1-(budding-uninhibited-by-benzimidazoles-1-homolog-(yeast))