Biology:BUB1B

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene.[1] 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

This gene encodes a kinase involved in spindle checkpoint function and chromosome segregation.[2] 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.[3]

Increased expression of BubR1 in mice extends a healthy lifespan.[4]

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.[4][5][6] 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.[5] 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.[7] 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.[7]

Interactions

BUB1B has been shown to interact with:

References

  1. ↑ "The mouse mitotic checkpoint gene bub1b, a novel bub1 family member, is expressed in a cell cycle-dependent manner". Genomics 55 (1): 113–117. January 1999. doi:10.1006/geno.1998.5629. PMID 9889005. 
  2. ↑ "CENP-E--dependent BubR1 autophosphorylation enhances chromosome alignment and the mitotic checkpoint". The Journal of Cell Biology 198 (2): 205–217. July 2012. doi:10.1083/jcb.201202152. PMID 22801780. 
  3. ↑ "Entrez Gene: BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=701. 
  4. ↑ 4.0 4.1 "Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan". Nature Cell Biology 15 (1): 96–102. January 2013. doi:10.1038/ncb2643. PMID 23242215. 
  5. ↑ 5.0 5.1 "BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice". Nature Genetics 36 (7): 744–749. July 2004. doi:10.1038/ng1382. PMID 15208629. 
  6. ↑ "Physiological relevance of post-translational regulation of the spindle assembly checkpoint protein BubR1". Cell & Bioscience 11 (1). April 2021. doi:10.1186/s13578-021-00589-2. PMID 33892776. 
  7. ↑ 7.0 7.1 "Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents". Oncogene 40 (43): 6210–6222. October 2021. doi:10.1038/s41388-021-02021-y. PMID 34545188. 
  8. ↑ 8.0 8.1 "The beta2-adaptin clathrin adaptor interacts with the mitotic checkpoint kinase BubR1". Biochemical and Biophysical Research Communications 298 (5): 720–730. November 2002. doi:10.1016/S0006-291X(02)02522-6. PMID 12419313. Bibcode: 2002BBRC..298..720C. 
  9. ↑ "Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1". Cancer Research 60 (6): 1531–1535. March 2000. PMID 10749118. 
  10. ↑ "A new view of the spindle checkpoint". The Journal of Cell Biology 154 (5): 909–911. September 2001. doi:10.1083/jcb.200108010. PMID 11535614. 
  11. ↑ "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. July 1998. doi:10.1083/jcb.142.1.1. PMID 9660858. 
  12. ↑ 12.0 12.1 "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. September 2001. doi:10.1083/jcb.200102093. PMID 11535616. 
  13. ↑ "Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex". Molecular Biology of the Cell 13 (3): 755–766. March 2002. doi:10.1091/mbc.01-09-0437. PMID 11907259. 
  14. ↑ "p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase". Oncogene 19 (40): 4557–4562. September 2000. doi:10.1038/sj.onc.1203803. PMID 11030144. 
  15. ↑ "Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells". The Journal of Cell Biology 158 (5): 841–847. September 2002. doi:10.1083/jcb.200201135. PMID 12196507. 
  16. ↑ "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. April 2001. doi:10.1073/pnas.081076898. PMID 11274370. Bibcode: 2001PNAS...98.4492S. 
  17. ↑ "The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction". Nature Cell Biology 10 (12): 1411–1420. December 2008. doi:10.1038/ncb1799. PMID 18997788. 
  18. ↑ 18.0 18.1 "SIRT2 induces the checkpoint kinase BubR1 to increase lifespan". The EMBO Journal 33 (13): 1438–1453. July 2014. doi:10.15252/embj.201386907. PMID 24825348. 
  19. ↑ "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. October 2014. doi:10.1016/j.bbrc.2014.09.128. PMID 25285631. Bibcode: 2014BBRC..453..588S. 
  20. ↑ "Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality". Aging Cell 17 (1). February 2018. doi:10.1111/acel.12698. PMID 29067790. 
  21. ↑ "Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit". The Journal of Cell Biology 183 (4): 667–680. November 2008. doi:10.1083/jcb.200805163. PMID 19015317. 
  22. ↑ "Polo-like kinase 1 facilitates chromosome alignment during prometaphase through BubR1" (in English). The Journal of Biological Chemistry 282 (20): 15217–15227. May 2007. doi:10.1074/jbc.M611053200. PMID 17376779. 
  23. ↑ "Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions". Genes & Development 21 (17): 2205–2219. September 2007. doi:10.1101/gad.436007. PMID 17785528. 
  24. ↑ "BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells". Oncogene 28 (31): 2806–2820. August 2009. doi:10.1038/onc.2009.141. PMID 19503101. 
  25. ↑ 25.0 25.1 "Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments" (in English). Developmental Cell 23 (4): 745–755. October 2012. doi:10.1016/j.devcel.2012.09.005. PMID 23079597. 
  26. ↑ "Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression". Journal of Cell Science 126 (Pt 5): 1086–1092. March 2013. doi:10.1242/jcs.122481. PMID 23345399. 
  27. ↑ "BUBR1 Pseudokinase Domain Promotes Kinetochore PP2A-B56 Recruitment, Spindle Checkpoint Silencing, and Chromosome Alignment" (in English). Cell Reports 33 (7). November 2020. doi:10.1016/j.celrep.2020.108397. PMID 33207204. 
  28. ↑ "Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization". Protein & Cell 7 (7): 516–526. July 2016. doi:10.1007/s13238-016-0283-4. PMID 27350047. 
  29. ↑ "WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase". FEBS Letters 575 (1–3): 23–29. September 2004. doi:10.1016/j.febslet.2004.07.089. PMID 15388328. Bibcode: 2004FEBSL.575...23Y. 
  30. ↑ "HDAC2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing". The FEBS Journal 284 (23): 4035–4050. December 2017. doi:10.1111/febs.14286. PMID 28985013. 
  31. ↑ "Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1". Oncogene 22 (48): 7593–7599. October 2003. doi:10.1038/sj.onc.1206880. PMID 14576821. 

Further reading





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