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BUB1B

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BUB1B
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesBUB1B,BUB1beta, BUBR1, Bub1A, MAD3L, MVA1, SSK1, hBUBR1, BUB1 mitotic checkpoint serine/threonine kinase B
External IDsOMIM:602860;MGI:1333889;HomoloGene:933;GeneCards:BUB1B;OMA:BUB1B - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 2: 118.43 – 118.47 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mitotic checkpoint serine/threonine-protein kinase BUB1 betais anenzymethat in humans is encoded by theBUB1Bgene.[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.

Function

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This gene encodes akinaseinvolved inspindle checkpointfunction andchromosome segregation.[6]The protein has been localized to thekinetochoreand plays a role in the inhibition of theanaphase-promoting complex/cyclosome(APC/C), delaying the onset ofanaphaseand ensuring properchromosomesegregation. 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

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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

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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 cancertumor 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 alternativenon-homologous end joining(A-NHEJ) that inaccurately repairs DNA damages such as those caused by the CRT. This inaccurate repair could cause additionalmutationsin the tumor including mutations to CRT resistance.[11]

Interactions

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BUB1B has been shown tointeractwith:

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000156970–Ensembl,May 2017
  2. ^abcGRCm38: 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.PMID9889005.
  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.PMC3410423.PMID22801780.
  7. ^"Entrez Gene: BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)".
  8. ^abBaker 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.PMC3707109.PMID23242215.
  9. ^abBaker 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.PMID15208629.S2CID7871496.
  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.PMC8066494.PMID33892776.
  11. ^abKomura 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.PMC8553621.PMID34545188.
  12. ^abCayrol 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.PMID12419313.
  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.PMID10749118.
  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.PMC2196198.PMID11535614.
  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.PMC2133037.PMID9660858.
  16. ^abSudakin 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.PMC2196190.PMID11535616.
  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.PMC99596.PMID11907259.
  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.PMID11030144.S2CID23544995.
  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.PMC2173153.PMID12196507.
  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.PMC31862.PMID11274370.
  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.PMC2635557.PMID18997788.
  22. ^abNorth 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.PMC4194088.PMID24825348.
  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.PMID25285631.
  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.PMC5770883.PMID29067790.
  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.PMC2582891.PMID19015317.
  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.PMID17376779.
  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.PMC1950859.PMID17785528.
  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.PMID19503101.S2CID23514072.
  29. ^abSuijkerbuijk 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.PMID23079597.
  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.PMID23345399.S2CID30718574.
  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.PMID33207204.S2CID227066402.
  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.PMC4930772.PMID27350047.
  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.PMID15388328.S2CID21762011.
  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.PMID28985013.S2CID4164003.
  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.PMID14576821.S2CID5689831.

Further reading

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