BUB1B

Last updated
BUB1B
Available structures
PDB Ortholog search: PDBe RCSB
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
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 Mb Chr 2: 118.43 – 118.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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:

Related Research Articles

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Kinetochore</span> Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

<span class="mw-page-title-main">Aurora kinase A</span> Protein-coding gene in the species Homo sapiens

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

<span class="mw-page-title-main">Aurora kinase B</span> Protein

Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere.

<span class="mw-page-title-main">CDC20</span> Protein-coding gene in the species Homo sapiens

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

<span class="mw-page-title-main">BUB1</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene.

<span class="mw-page-title-main">MAD2L1</span> Protein-coding gene in the species Homo sapiens

Mitotic spindle assembly checkpoint protein MAD2A is a protein that in humans is encoded by the MAD2L1 gene.

<span class="mw-page-title-main">CDC27</span> Protein-coding gene in the species Homo sapiens

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 gene.

<span class="mw-page-title-main">NEK2</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Nek2 is an enzyme that in humans is encoded by the NEK2 gene.

<span class="mw-page-title-main">NDC80</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein NDC80 homolog is a protein that in humans is encoded by the NDC80 gene.

<span class="mw-page-title-main">Centromere protein E</span> Centromere- and microtubule-associated protein

Centromere-associated protein E is a protein that in humans is encoded by the CENPE gene.

<span class="mw-page-title-main">CDC16</span> Protein-coding gene in the species Homo sapiens

Cell division cycle protein 16 homolog is a protein that in humans is encoded by the CDC16 gene.

<span class="mw-page-title-main">BUB3</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.

<span class="mw-page-title-main">NUF2</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein Nuf2 is a protein that in humans is encoded by the NUF2 gene.

<span class="mw-page-title-main">ZW10</span>

Centromere/kinetochore protein zw10 homolog is a protein that in humans is encoded by the ZW10 gene. This gene encodes a protein that is one of many involved in mechanisms to ensure proper chromosome segregation during cell division. The encoded protein binds to centromeres during the prophase, metaphase, and early anaphase cell division stages and to kinetochore microtubules during metaphase.

<span class="mw-page-title-main">Shugoshin 1</span> Protein-coding gene in the species Homo sapiens

Shugoshin 1 or Shugoshin-like 1, is a protein that in humans is encoded by the SGO1 gene.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000156970 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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.
  9. 1 2 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. 1 2 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. 1 2 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. 1 2 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. 1 2 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. 1 2 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.

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