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BUB3 (BUB3 mitotic checkpoint protein)

Written2019-03Jorge Antonio Elias Godoy Carlos, João Agostinho Machado-Neto
Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil; jorgegdy@icloud.com; jamachadoneto@usp.br

Abstract BUB3 is a WD40 protein that belongs to spindle mitotic checkpoint complex, which monitors the chromosome attachment to mitotic (or meiotic) fuse and prevents premature chromosome segregation. Alterations in BUB3 have been associated with chromosomal instability and aneuploidy, but their contribution for cancer development and progression are poorly understood, and appear to differ depending on the type of cancer. The present review contains data on BUB3 DNA, RNA, protein encoded and function.

Keywords BUB3; Mitotic checkpoint protein BUB3; WD40 protein; Spindle checkpoint; Cell cycle; Anaphase-promoting complex.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesBUB3 (budding uninhibited by benzimidazoles 3, yeast) homolog
budding uninhibited by benzimidazoles 3 homolog (yeast)
Alias_symbol (synonym)BUB3L
Other aliashBUB3
HGNC (Hugo) BUB3
LocusID (NCBI) 9184
Atlas_Id 855
Location 10q26.13  [Link to chromosome band 10q26]
Location_base_pair Starts at 123154244 and ends at 123165370 bp from pter ( according to hg19-Feb_2009)  [Mapping BUB3.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

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

Protein

 
  Figure 1. BUB3 protein structure. BUB3 protein presents seven WD40 repeat domain, a nearly 40 amino acids (aa) motif rich in tryptophan-aspartic acids (W-D). The position of aa are indicated.
Description 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.
Expression Ubiquitous.
Localisation 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).
 
  Figure 2. BUB3, a component of mitotic checkpoint complex (MCC). (Upper panel) The presence of unattached kinotochores induces the formation of MCC composed by BUB3, BUBR1, MAD2L1, which sequester CDC20, leads the anaphase-promoting complex/cyclosome (APC/C) inhibition and cell cycle arrest. (Lower panel) In the presence of attached kinotochores, the MCC complex is disassembled and the CDC20 is released, which leads to APC/C activation (which in turn triggers degradation of securin and cyclin B), chromosomal segregation and completion of mitosis.
Function 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.
Homology 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  SymbolProtein  DNA
vs. P.troglodytesBUB3100.099.8
vs. M.mulattaBUB3100.098.8
vs. B.taurusBUB3100.093.5
vs. M.musculusBub3100.090.4
vs. R.norvegicusBub3100.091.1
vs. G.gallusBUB396.984.0
vs. X.tropicalisbub393.279.5
vs. D.reriobub386.273.7
vs. D.melanogasterBub361.159.9
vs. A.gambiaeAgaP_AGAP01054462.059.2
vs. S.pombebub338.045.0
vs. A.thalianaBUB3.155.155.0
vs. A.thalianaBUB3.256.355.8
vs. O.sativaOs03g044860056.357.4

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

Mutations

Somatic 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).

Implicated in

  
Entity Adrenocortical carcinoma
Note In a cohort of 79 adrenocortical carcinoma patients, increased levels of BUB3 mRNA levels was associated with high grade tumors and poor clinical outcomes (Subramanian and Cohen, 2019). In addition, Oncomine Giordano ACC data analysis revealed increased levels of BUB3 in adrenocortical carcinoma compared to normal adrenal samples (Subramanian and Cohen, 2019).
  
  
Entity Breast cancer
Note BUB3 promoter polymorphisms (rs3763740, rs3763741, rs17014712, rs3808960 and rs3808961) did not impact familial breast cancer risk in a German cohort of 441 breast cancer patients and 552 controls matched by age, ethnicity and geographical region (Vaclavicek et al., 2007). Similarly, the polymorphisms rs11248416, rs11248419, and rs6599657 in BUB3 gene were not associated with risk of breast cancer development in a Chinese cohort of 462 breast cancer patients and 529 controls (Wang et al., 2014).
BUB3 was highly expressed in primary and cell lines from breast cancer compared to immortalized breast cancer epithelium or normal primary mammary cells (Yuan et al., 2006). BUB3 gene region (10q26.3) was found to be amplified and overexpressed in breast cancer samples (Turner et al., 2010). BUB3 mRNA levels were upregulated in doxorubicin and cyclophosphamide sensitive breast cancer tumors (Cleator et al., 2006). In MDA-MB-231 breast cancer cells, BUB3 expression was induced by BMP signaling (Yan et al., 2012).
  
  
Entity Cervical cancer
Note Using proteomics approach, BUB3 was found to be downregulated by paclitaxel and 5-fluorouracil in HeLa cells (Lee et al., 2005; Yim et al., 2004). In addition, BUB3 inhibition by siRNA reduced paclitaxel-induced cell cycle arrest (Lee et al., 2005).
  
  
Entity Chronic myeloid leukemia
Note BCR/ ABL1 expression repressed spindle checkpoint components, including BUB3, to escape from metaphase arrest (Wolanin et al., 2010).
  
  
Entity Colorectal cancer
Note Three missense variants in BUB3 [predicted to be pathogenic: c.790T>C (p.F264L), c.63G>C (p.K21N) and c.446G>A (p.R149Q)] were observed in familial or early onset colorectal cancer patients (n=185), which were not found in large cohort of control (n=1154) (de Voer et al., 2013). In agreement, Mur and colleagues (Mur et al., 2018) reported that BUB3 was found to be mutated [BUB3 c.77C>T (p.T26I)] in familial colorectal cancer.
  
  
Entity Gastric cancer
Note High BUB3 gene expression was observed in 34 out of 43 gastric cancer tumors samples compared with their matched normal mucosa counterpart, which was associated with Ki-67 expression, but not with aneuploidy (Grabsch et al., 2003). The BUB3 polymorphism, rs7897156, did not impact gastric cancer susceptibility in a study including 164 gastric cancer patients and 381 ethnicity matched controls (Mesic et al., 2017).
  
  
Entity Glioblastoma
Note he genetic variation C>T in the position -6 of the BUB3 gene, but not in coding sequence, was detected in 4 out of 22 glioblastoma samples (Reis et al., 2001). Bie and colleagues (Bie et al., 2011) reported that BUB3 was highly expressed in grade III and IV gliomas compared to normal brain samples. On the other hand, Morales and colleagues (Morales et al., 2013) reported a downregulation of BUB3 in primary samples and cell lines derived from glioblastoma compared to non-neoplastic white matter from epileptic patients.
In BUB3-depleted U87MG glioblastoma cells, the expression o BUB3Y207F, which mimics an unphosphorylated form, strongly reduced tumor growth and improved survival compared to the expression BUB3WT in intracranial tumor mice model, indicating that BUB3 phosphorylation at Y207 site is required for tumorigenesis (Jiang et al., 2014).
  
  
Entity Lung cancer
Note Initial observations did not identify genetic defects in BUB3 gene in lung cancer patients (Haruki et al., 2001). In cohort of 766 non-small cell lung cancer patients, the presence of allele T of polymorphism in BUB3 (rs7897156C>T) was associated with poor overall survival (Kang et al., 2017). Using H1299 and A549 non-small cell lung cell lines, functional studies based in luciferase assays indicated that T allele induced enhancement of BUB3 expression. In addition, increased BUB3 expression was observed in lung tumor tissues compared to non-malignant lung tissues (Kang et al., 2017).
  
  
Entity Osteosarcoma
Note Loss of heterozygosity at 10q26, but not BUB3 mutations, was found in ostesarcoma samples (Mendoza et al., 2005). In Saos-2 osteosarcoma cells, TAp73α (an isoform of TP73) binds to BUB3 and BUB1, which leads to potential alteration of mitotic checkpoint function of these proteins and aneuploidy (Vernole et al., 2009). In U2OS osteosarcoma cells, but not normal fibroblast, BUB3 silencing reduces cell proliferation and clonogenicity and induces DNA fragmentation (Prinz et al., 2016).
  
  
Entity Ovarian cystadenoma
Note In ML10 cells, a human ovarian cystadenoma model, BUB3 nuclear expression and phosphorylation were increased in low compared to high replicative age cells, which may be involved in prolonged mitotic arrest and cytokinesis failure observed in this cellular model (Austria et al., 2018).
  
  
Entity Pancreatic cancer
Note A mutation in BUB3 (c.576+1G>A) was found among deleterious germline mutations (n=33) in sporadic pancreatic adenocarcinoma patients (n=854) (Shindo et al., 2017). In pancreatic cells, DMAP1/BUB3 complex repressed antiapoptotic genes transcription mediating mitotic stress-induced apoptosis and improved in vivo paclitaxel-induced tumor growth inhibition, which are impaired by SRC activity (Li et al., 2018).
  
  
Entity Renal cell carcinoma
Note BUB3 gene expression profile was similar between samples from papillary renal cell carcinoma, chromophobe renal cell carcinoma and clear cell renal cell carcinoma patients and normal kidney tissues (Pinto et al., 2007; Pinto et al., 2008).
  

To be noted

BUB3 knockout mice presented accumulation of mitotic errors during embryogenesis and were unviable after day 6.5-7.5 postcoitus (Kalitsis et al., 2000). BUB3 haploinsufficiency leaded to chromosome instability and predisposition to carcinogen-induced, but not to spontaneous, tumors development in mice (Babu et al., 2003; Kalitsis et al., 2005; Rao et al., 2009). Induced-BUB3 mutations presented no effect on the genome rearrangements rate in Saccharomyces cerevisiae (Myung et al., 2001). In healthy humans, BUB3 genetic variations were not associated with non-specific chromosomal aberrations (Forsti et al., 2016).

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Citation

This paper should be referenced as such :
Elias Godoy Carlos JA, Machado-Neto J
BUB3 (BUB3 mitotic checkpoint protein);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/BUB3ID855ch10q26.html


External links

Nomenclature
HGNC (Hugo)BUB3   1151
Cards
AtlasBUB3ID855ch10q26
Entrez_Gene (NCBI)BUB3  9184  BUB3 mitotic checkpoint protein
AliasesBUB3L; hBUB3
GeneCards (Weizmann)BUB3
Ensembl hg19 (Hinxton)ENSG00000154473 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000154473 [Gene_View]  ENSG00000154473 [Sequence]  chr10:123154244-123165370 [Contig_View]  BUB3 [Vega]
ICGC DataPortalENSG00000154473
TCGA cBioPortalBUB3
AceView (NCBI)BUB3
Genatlas (Paris)BUB3
WikiGenes9184
SOURCE (Princeton)BUB3
Genetics Home Reference (NIH)BUB3
Genomic and cartography
GoldenPath hg38 (UCSC)BUB3  -     chr10:123154244-123165370 +  10q26.13   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)BUB3  -     10q26.13   [Description]    (hg19-Feb_2009)
GoldenPathBUB3 - 10q26.13 [CytoView hg19]  BUB3 - 10q26.13 [CytoView hg38]
ImmunoBaseENSG00000154473
Mapping of homologs : NCBIBUB3 [Mapview hg19]  BUB3 [Mapview hg38]
OMIM603719   
Gene and transcription
Genbank (Entrez)AF047472 AF047473 AF053304 AF081496 AK226060
RefSeq transcript (Entrez)NM_001007793 NM_004725
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)BUB3
Cluster EST : UnigeneHs.418533 [ NCBI ]
CGAP (NCI)Hs.418533
Alternative Splicing GalleryENSG00000154473
Gene ExpressionBUB3 [ NCBI-GEO ]   BUB3 [ EBI - ARRAY_EXPRESS ]   BUB3 [ SEEK ]   BUB3 [ MEM ]
Gene Expression Viewer (FireBrowse)BUB3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9184
GTEX Portal (Tissue expression)BUB3
Human Protein AtlasENSG00000154473-BUB3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO43684   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO43684  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO43684
Splice isoforms : SwissVarO43684
PhosPhoSitePlusO43684
Domaine pattern : Prosite (Expaxy)WD_REPEATS_2 (PS50082)    WD_REPEATS_REGION (PS50294)   
Domains : Interpro (EBI)G-protein_beta_WD-40_rep    WD40/YVTN_repeat-like_dom_sf    WD40_repeat    WD40_repeat_dom    WD40_repeat_dom_sf   
Domain families : Pfam (Sanger)WD40 (PF00400)   
Domain families : Pfam (NCBI)pfam00400   
Domain families : Smart (EMBL)WD40 (SM00320)  
Conserved Domain (NCBI)BUB3
DMDM Disease mutations9184
Blocks (Seattle)BUB3
SuperfamilyO43684
Human Protein Atlas [tissue]ENSG00000154473-BUB3 [tissue]
Peptide AtlasO43684
HPRD04761
IPIIPI00013468   IPI00514701   IPI01010654   IPI00644568   IPI00644108   
Protein Interaction databases
DIP (DOE-UCLA)O43684
IntAct (EBI)O43684
FunCoupENSG00000154473
BioGRIDBUB3
STRING (EMBL)BUB3
ZODIACBUB3
Ontologies - Pathways
QuickGOO43684
Ontology : AmiGOmitotic sister chromatid segregation  kinetochore  kinetochore  condensed chromosome kinetochore  protein binding  nucleoplasm  cytosol  ubiquitin-dependent protein catabolic process  mitotic spindle assembly checkpoint  attachment of spindle microtubules to kinetochore  anaphase-promoting complex-dependent catabolic process  mitotic checkpoint complex  protein localization to kinetochore  ubiquitin binding  cell division  meiotic cell cycle  regulation of mitotic cell cycle phase transition  bub1-bub3 complex  
Ontology : EGO-EBImitotic sister chromatid segregation  kinetochore  kinetochore  condensed chromosome kinetochore  protein binding  nucleoplasm  cytosol  ubiquitin-dependent protein catabolic process  mitotic spindle assembly checkpoint  attachment of spindle microtubules to kinetochore  anaphase-promoting complex-dependent catabolic process  mitotic checkpoint complex  protein localization to kinetochore  ubiquitin binding  cell division  meiotic cell cycle  regulation of mitotic cell cycle phase transition  bub1-bub3 complex  
Pathways : KEGGCell cycle    HTLV-I infection   
REACTOMEO43684 [protein]
REACTOME PathwaysR-HSA-68877 [pathway]   
NDEx NetworkBUB3
Atlas of Cancer Signalling NetworkBUB3
Wikipedia pathwaysBUB3
Orthology - Evolution
OrthoDB9184
GeneTree (enSembl)ENSG00000154473
Phylogenetic Trees/Animal Genes : TreeFamBUB3
HOGENOMO43684
Homologs : HomoloGeneBUB3
Homology/Alignments : Family Browser (UCSC)BUB3
Gene fusions - Rearrangements
Fusion : FusionGDB29469   
Fusion : Fusion_HubAL160290.2--BUB3    BUB3--CMC4    BUB3--DIP2B    BUB3--DOCK1    BUB3--IL1R2    BUB3--MXI1    BUB3--RNASET2    BUB3--SMAP2    BUB3--TACC2    BUBR1--BUB3    FSTL1--BUB3    FYB--BUB3    HSPA9--BUB3    IQGAP2--BUB3    NAE1--BUB3   
NDUFA13--BUB3    PTPN9--BUB3    THBS1--BUB3    YBX3--BUB3    ZFP91--BUB3   
Fusion : QuiverBUB3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBUB3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)BUB3
dbVarBUB3
ClinVarBUB3
1000_GenomesBUB3 
Exome Variant ServerBUB3
ExAC (Exome Aggregation Consortium)ENSG00000154473
GNOMAD BrowserENSG00000154473
Varsome BrowserBUB3
Genetic variants : HAPMAP9184
Genomic Variants (DGV)BUB3 [DGVbeta]
DECIPHERBUB3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBUB3 
Mutations
ICGC Data PortalBUB3 
TCGA Data PortalBUB3 
Broad Tumor PortalBUB3
OASIS PortalBUB3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBUB3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DBUB3
Mutations and Diseases : HGMDBUB3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch BUB3
DgiDB (Drug Gene Interaction Database)BUB3
DoCM (Curated mutations)BUB3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BUB3 (select a term)
intoGenBUB3
NCG5 (London)BUB3
Cancer3DBUB3(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603719   
Orphanet1351   
DisGeNETBUB3
MedgenBUB3
Genetic Testing Registry BUB3
NextProtO43684 [Medical]
TSGene9184
GENETestsBUB3
Target ValidationBUB3
Huge Navigator BUB3 [HugePedia]
snp3D : Map Gene to Disease9184
BioCentury BCIQBUB3
ClinGenBUB3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9184
Chemical/Pharm GKB GenePA25467
Clinical trialBUB3
Miscellaneous
canSAR (ICR)BUB3 (select the gene name)
DataMed IndexBUB3
Probes
Litterature
PubMed131 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineBUB3
EVEXBUB3
GoPubMedBUB3
iHOPBUB3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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