BUB1B

Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene.^[5] Also known as BubR1, this protein is recognized for its mitotic roles in the spindle assembly checkpoint (SAC) and kinetochore-microtubule interactions that facilitate chromosome migration and alignment. BubR1 promotes mitotic fidelity and protects against aneuploidy by ensuring proper chromosome segregation between daughter cells. BubR1 is proposed to prevent tumorigenesis.

BUB1B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2WVI, 3SI5, 4GGD, 5JJA
Identifiers
Aliases	BUB1B, BUB1beta, BUBR1, Bub1A, MAD3L, MVA1, SSK1, hBUBR1, BUB1 mitotic checkpoint serine/threonine kinase B
External IDs	OMIM: 602860; MGI: 1333889; HomoloGene: 933; GeneCards: BUB1B; OMA:BUB1B - orthologs
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q15.1 Start 40,161,023 bp[1] End 40,221,123 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 E5 Start 118,428,692 bp[2] End 118,472,072 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte ventricular zone gonad embryo Epithelium of choroid plexus ganglionic eminence right testis bone marrow left testis trabecular bone Top expressed in secondary oocyte primary oocyte ectoderm otic vesicle primitive streak otic placode tail of embryo spermatocyte genital tubercle zygote More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein serine/threonine kinase activity ATP binding protein binding kinase activity nucleotide binding transferase activity protein kinase activity Cellular component kinetochore nucleus cytoskeleton outer kinetochore microtubule organizing center perinuclear region of cytoplasm chromosome, centromeric region anaphase-promoting complex chromosome cytoplasm spindle midzone cytosol spindle Biological process protein localization to chromosome, centromeric region anaphase-promoting complex-dependent catabolic process mitotic cell cycle checkpoint signaling protein phosphorylation metaphase cell cycle apoptotic process phosphorylation cell division cell population proliferation protein localization to kinetochore mitotic spindle assembly checkpoint signaling meiotic sister chromatid cohesion, centromeric mitotic cell cycle regulation of mitotic cell cycle phase transition ubiquitin-dependent protein catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 701 12236 Ensembl ENSG00000156970 ENSMUSG00000040084 UniProt O60566 Q9Z1S0 RefSeq (mRNA) NM_001211 NM_009773 RefSeq (protein) NP_001202 NP_033903 Location (UCSC) Chr 15: 40.16 – 40.22 Mb Chr 2: 118.43 – 118.47 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

This gene encodes a kinase involved in spindle checkpoint function and chromosome segregation.^[6] The protein has been localized to the kinetochore and plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Impaired spindle checkpoint function has been found in many forms of cancer.^[7]

Increased expression of BubR1 in mice extends a healthy lifespan.^[8]

Clinical Significance

BubR1 has been implicated in a variety of biological processes and pathologies, including cancer, aging, mosaic variegated aneuploidy (MVA), and heart disease. BubR1 protein levels are shown to decline with age.^[8][9][10] Furthermore, loss of BubR1 in young organisms is associated with rapid aging and premature onset of age-related diseases and phenotypes such as cardiac dysfunction, poor wound healing, cataracts, kyphosis, fat loss and muscle wasting (cachexia), and cancer.^[9] This has been demonstrated in mice.

DNA repair

Chemoradiotherapy (CRT), the combination of chemotherapy and radiotherapy applied with curative intent, is used to treat a variety of cancers. CRT acts by inducing damage in the DNA of the cancer cells. Bladder cancer tumor samples were taken from patients before treatment and from the same patients after CRT treatment when the tumors had reoccurred.^[11] An increased level of BUB1B expression was found in the CRT-recurrent cells. This increased expression was considered to facilitate an inaccurate DNA repair process termed alternative non-homologous end joining (A-NHEJ) that inaccurately repairs DNA damages such as those caused by the CRT. This inaccurate repair could cause additional mutations in the tumor including mutations to CRT resistance.^[11]

Interactions

BUB1B has been shown to interact with:

• AP2B1^[12]
• BRCA2^[13]
• BUB3^[12][14][15]
• CDC20^{[16][17][18][19][20][21]}
• MAD2L1^[16]
• CBP^[22]
• SIRT2^[22][23][24]
• PLK1^{[25][26][27][28][29]}
• PP2A-B56^{[29][30][31][32]}
• HDAC1^[33]
• HDAC2 / HDAC3^[34]
• SNCG^[35]

References

1. GRCh38: Ensembl release 89: ENSG00000156970 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040084 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Davenport JW, Fernandes ER, Harris LD, Neale GA, Goorha R (January 1999). "The mouse mitotic checkpoint gene bub1b, a novel bub1 family member, is expressed in a cell cycle-dependent manner". Genomics. 55 (1): 113–117. doi:10.1006/geno.1998.5629. PMID 9889005.
6. Guo Y, Kim C, Ahmad S, Zhang J, Mao Y (July 2012). "CENP-E--dependent BubR1 autophosphorylation enhances chromosome alignment and the mitotic checkpoint". The Journal of Cell Biology. 198 (2): 205–217. doi:10.1083/jcb.201202152. PMC 3410423. PMID 22801780.
7. "Entrez Gene: BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)".
8. Baker DJ, Dawlaty MM, Wijshake T, Jeganathan KB, Malureanu L, van Ree JH, et al. (January 2013). "Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan". Nature Cell Biology. 15 (1): 96–102. doi:10.1038/ncb2643. PMC 3707109. PMID 23242215.

   • "Mayo Clinic Study Unmasks Regulator of Healthy Life Span". Mayo Clinic. December 17, 2012.
9. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, et al. (July 2004). "BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice". Nature Genetics. 36 (7): 744–749. doi:10.1038/ng1382. PMID 15208629. S2CID 7871496.
10. Bloom CR, North BJ (April 2021). "Physiological relevance of post-translational regulation of the spindle assembly checkpoint protein BubR1". Cell & Bioscience. 11 (1): 76. doi:10.1186/s13578-021-00589-2. PMC 8066494. PMID 33892776.
11. Komura K, Inamoto T, Tsujino T, Matsui Y, Konuma T, Nishimura K, et al. (October 2021). "Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents". Oncogene. 40 (43): 6210–6222. doi:10.1038/s41388-021-02021-y. PMC 8553621. PMID 34545188.
12. Cayrol C, Cougoule C, Wright M (November 2002). "The beta2-adaptin clathrin adaptor interacts with the mitotic checkpoint kinase BubR1". Biochemical and Biophysical Research Communications. 298 (5): 720–730. doi:10.1016/S0006-291X(02)02522-6. PMID 12419313.
13. Futamura M, Arakawa H, Matsuda K, Katagiri T, Saji S, Miki Y, Nakamura Y (March 2000). "Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1". Cancer Research. 60 (6): 1531–1535. PMID 10749118.
14. Hoyt MA (September 2001). "A new view of the spindle checkpoint". The Journal of Cell Biology. 154 (5): 909–911. doi:10.1083/jcb.200108010. PMC 2196198. PMID 11535614.
15. Taylor SS, Ha E, McKeon F (July 1998). "The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase". The Journal of Cell Biology. 142 (1): 1–11. doi:10.1083/jcb.142.1.1. PMC 2133037. PMID 9660858.
16. Sudakin V, Chan GK, Yen TJ (September 2001). "Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2". The Journal of Cell Biology. 154 (5): 925–936. doi:10.1083/jcb.200102093. PMC 2196190. PMID 11535616.
17. Fang G (March 2002). "Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex". Molecular Biology of the Cell. 13 (3): 755–766. doi:10.1091/mbc.01-09-0437. PMC 99596. PMID 11907259.
18. Wu H, Lan Z, Li W, Wu S, Weinstein J, Sakamoto KM, Dai W (September 2000). "p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase". Oncogene. 19 (40): 4557–4562. doi:10.1038/sj.onc.1203803. PMID 11030144. S2CID 23544995.
19. Kallio MJ, Beardmore VA, Weinstein J, Gorbsky GJ (September 2002). "Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells". The Journal of Cell Biology. 158 (5): 841–847. doi:10.1083/jcb.200201135. PMC 2173153. PMID 12196507.
20. Skoufias DA, Andreassen PR, Lacroix FB, Wilson L, Margolis RL (April 2001). "Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints". Proceedings of the National Academy of Sciences of the United States of America. 98 (8): 4492–4497. Bibcode:2001PNAS...98.4492S. doi:10.1073/pnas.081076898. PMC 31862. PMID 11274370.
21. Nilsson J, Yekezare M, Minshull J, Pines J (December 2008). "The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction". Nature Cell Biology. 10 (12): 1411–1420. doi:10.1038/ncb1799. PMC 2635557. PMID 18997788.
22. North BJ, Rosenberg MA, Jeganathan KB, Hafner AV, Michan S, Dai J, et al. (July 2014). "SIRT2 induces the checkpoint kinase BubR1 to increase lifespan". The EMBO Journal. 33 (13): 1438–1453. doi:10.15252/embj.201386907. PMC 4194088. PMID 24825348.
23. Suematsu T, Li Y, Kojima H, Nakajima K, Oshimura M, Inoue T (October 2014). "Deacetylation of the mitotic checkpoint protein BubR1 at lysine 250 by SIRT2 and subsequent effects on BubR1 degradation during the prometaphase/anaphase transition". Biochemical and Biophysical Research Communications. 453 (3): 588–594. doi:10.1016/j.bbrc.2014.09.128. PMID 25285631.
24. Qiu D, Hou X, Han L, Li X, Ge J, Wang Q (February 2018). "Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality". Aging Cell. 17 (1): e12698. doi:10.1111/acel.12698. PMC 5770883. PMID 29067790.
25. Huang H, Hittle J, Zappacosta F, Annan RS, Hershko A, Yen TJ (November 2008). "Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit". The Journal of Cell Biology. 183 (4): 667–680. doi:10.1083/jcb.200805163. PMC 2582891. PMID 19015317.
26. Matsumura S, Toyoshima F, Nishida E (May 2007). "Polo-like kinase 1 facilitates chromosome alignment during prometaphase through BubR1". The Journal of Biological Chemistry. 282 (20): 15217–15227. doi:10.1074/jbc.M611053200. PMID 17376779.
27. Elowe S, Hümmer S, Uldschmid A, Li X, Nigg EA (September 2007). "Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions". Genes & Development. 21 (17): 2205–2219. doi:10.1101/gad.436007. PMC 1950859. PMID 17785528.
28. Izumi H, Matsumoto Y, Ikeuchi T, Saya H, Kajii T, Matsuura S (August 2009). "BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells". Oncogene. 28 (31): 2806–2820. doi:10.1038/onc.2009.141. PMID 19503101. S2CID 23514072.
29. Suijkerbuijk SJ, Vleugel M, Teixeira A, Kops GJ (October 2012). "Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments". Developmental Cell. 23 (4): 745–755. doi:10.1016/j.devcel.2012.09.005. PMID 23079597.
30. Kruse T, Zhang G, Larsen MS, Lischetti T, Streicher W, Kragh Nielsen T, et al. (March 2013). "Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression". Journal of Cell Science. 126 (Pt 5): 1086–1092. doi:10.1242/jcs.122481. PMID 23345399. S2CID 30718574.
31. Gama Braga L, Cisneros AF, Mathieu MM, Clerc M, Garcia P, Lottin B, et al. (November 2020). "BUBR1 Pseudokinase Domain Promotes Kinetochore PP2A-B56 Recruitment, Spindle Checkpoint Silencing, and Chromosome Alignment". Cell Reports. 33 (7): 108397. doi:10.1016/j.celrep.2020.108397. PMID 33207204. S2CID 227066402.
32. Wang J, Wang Z, Yu T, Yang H, Virshup DM, Kops GJ, et al. (July 2016). "Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization". Protein & Cell. 7 (7): 516–526. doi:10.1007/s13238-016-0283-4. PMC 4930772. PMID 27350047.
33. Yoon YM, Baek KH, Jeong SJ, Shin HJ, Ha GH, Jeon AH, et al. (September 2004). "WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase". FEBS Letters. 575 (1–3): 23–29. doi:10.1016/j.febslet.2004.07.089. PMID 15388328. S2CID 21762011.
34. Park I, Kwon MS, Paik S, Kim H, Lee HO, Choi E, Lee H (December 2017). "HDAC2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing". The FEBS Journal. 284 (23): 4035–4050. doi:10.1111/febs.14286. PMID 28985013. S2CID 4164003.
35. Gupta A, Inaba S, Wong OK, Fang G, Liu J (October 2003). "Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1". Oncogene. 22 (48): 7593–7599. doi:10.1038/sj.onc.1206880. PMID 14576821. S2CID 5689831.

Further reading

• Posas F, Saito H (March 1998). "Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator". The EMBO Journal. 17 (5): 1385–1394. doi:10.1093/emboj/17.5.1385. PMC 1170486. PMID 9482735.
• Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, et al. (March 1998). "Mutations of mitotic checkpoint genes in human cancers". Nature. 392 (6673): 300–303. Bibcode:1998Natur.392..300C. doi:10.1038/32688. PMID 9521327. S2CID 4416376.
• Donadelli R, Benatti L, Remuzzi A, Morigi M, Gullans SR, Benigni A, et al. (May 1998). "Identification of a novel gene--SSK1--in human endothelial cells exposed to shear stress". Biochemical and Biophysical Research Communications. 246 (3): 881–887. doi:10.1006/bbrc.1998.8713. PMID 9618306.
• Chan GK, Schaar BT, Yen TJ (October 1998). "Characterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F and hBUBR1". The Journal of Cell Biology. 143 (1): 49–63. doi:10.1083/jcb.143.1.49. PMC 2132809. PMID 9763420.
• Jablonski SA, Chan GK, Cooke CA, Earnshaw WC, Yen TJ (December 1998). "The hBUB1 and hBUBR1 kinases sequentially assemble onto kinetochores during prophase with hBUBR1 concentrating at the kinetochore plates in mitosis". Chromosoma. 107 (6–7): 386–396. doi:10.1007/s004120050322. PMID 9914370. S2CID 13928165.
• Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C (June 1999). "Characterization of MAD2B and other mitotic spindle checkpoint genes". Genomics. 58 (2): 181–187. doi:10.1006/geno.1999.5831. PMID 10366450.
• Chan GK, Jablonski SA, Sudakin V, Hittle JC, Yen TJ (September 1999). "Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC". The Journal of Cell Biology. 146 (5): 941–954. doi:10.1083/jcb.146.5.941. PMC 2169490. PMID 10477750.
• Li W, Lan Z, Wu H, Wu S, Meadows J, Chen J, et al. (November 1999). "BUBR1 phosphorylation is regulated during mitotic checkpoint activation". Cell Growth & Differentiation. 10 (11): 769–775. PMID 10593653.
• Saffery R, Irvine DV, Griffiths B, Kalitsis P, Choo KH (October 2000). "Components of the human spindle checkpoint control mechanism localize specifically to the active centromere on dicentric chromosomes". Human Genetics. 107 (4): 376–384. doi:10.1007/s004390000386. PMID 11129339. S2CID 38578162.
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (September 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–292. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
• Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Näthke IS (April 2001). "A role for the Adenomatous Polyposis Coli protein in chromosome segregation". Nature Cell Biology. 3 (4): 429–432. doi:10.1038/35070123. PMID 11283619. S2CID 12645435.
• Tang Z, Bharadwaj R, Li B, Yu H (August 2001). "Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1". Developmental Cell. 1 (2): 227–237. doi:10.1016/S1534-5807(01)00019-3. PMID 11702782.
• Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y (January 2002). "Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival". Cancer Research. 62 (1): 13–17. PMID 11782350.
• Taylor SS, Hussein D, Wang Y, Elderkin S, Morrow CJ (December 2001). "Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells". Journal of Cell Science. 114 (Pt 24): 4385–4395. doi:10.1242/jcs.114.24.4385. PMID 11792804.

External links

• Human BUB1B genome location and BUB1B gene details page in the UCSC Genome Browser.