View source for BUB1

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Mitotic checkpoint serine/threonine-protein kinase BUB1''' also known as '''BUB1'''  (budding uninhibited by benzimidazoles 1) is an [[enzyme]] that in humans is encoded by the ''BUB1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=699}}</ref><ref name="pmid9521327">{{cite journal | vauthors = Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B | title = Mutations of mitotic checkpoint genes in human cancers | journal = Nature | volume = 392 | issue = 6673 | pages = 300–3 | date = Mar 1998 | pmid = 9521327 | doi = 10.1038/32688 | bibcode = 1998Natur.392..300C | s2cid = 4416376 }}</ref>
Bub1 is a [[serine/threonine protein kinase]] first identified in genetic screens of ''[[Saccharomyces cerevisiae]] (baker's yeast)''.<ref name="pmid7969164">{{cite journal | vauthors = Roberts BT, Farr KA, Hoyt MA | title = The Saccharomyces cerevisiae checkpoint gene BUB1 encodes a novel protein kinase | journal = Molecular and Cellular Biology | volume = 14 | issue = 12 | pages = 8282–91 | date = Dec 1994 | pmid = 7969164 | pmc = 359367 | doi =  10.1128/mcb.14.12.8282}}</ref> The protein is bound to [[kinetochore]]s and plays a key role in the establishment of the [[spindle checkpoint|mitotic spindle checkpoint]] and chromosome congression. The mitotic checkpoint kinase is evolutionarily conserved in organisms as diverse as ''[[Saccharomyces cerevisiae]]'' and humans. Loss-of-function mutations or absence of Bub1 has been reported to result in [[aneuploidy]], chromosomal instability ([[chromosome instability syndrome|CIN]]) and premature [[senescence]].
== Structure ==
Bub1p comprises a conserved [[N-terminus|N-terminal]] region, a central non-conserved region and a [[C-terminus|C-terminal]] serine/threonine kinase domain.<ref name="pmid19141287">{{cite journal | vauthors = Bolanos-Garcia VM, Kiyomitsu T, D'Arcy S, Chirgadze DY, Grossmann JG, Matak-Vinkovic D, Venkitaraman AR, Yanagida M, Robinson CV, Blundell TL | title = The crystal structure of the N-terminal region of BUB1 provides insight into the mechanism of BUB1 recruitment to kinetochores | journal = Structure | volume = 17 | issue = 1 | pages = 105–16 | date = Jan 2009 | pmid = 19141287 | pmc = 2683949 | doi = 10.1016/j.str.2008.10.015 }}</ref> The N-terminal region mediates binding of Hs-BUB1 to the mitotic kinetochore protein blinkin (a protein also commonly referred to as AF15q14). The latter interaction is essential for kinetochore localization of Bub1 and its function in cell cycle arrest induced by [[spindle checkpoint|spindle assembly checkpoint]] (SAC) activation.<ref name="pmid17981135">{{cite journal | vauthors = Kiyomitsu T, Obuse C, Yanagida M | title = Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1 | journal = Developmental Cell | volume = 13 | issue = 5 | pages = 663–76 | date = Nov 2007 | pmid = 17981135 | doi = 10.1016/j.devcel.2007.09.005 | doi-access = free }}</ref>  The crystal structure of human Bub1 revealed the presence of a N-terminal [[tetratricopeptide]] repeat (TPR) domain and a C-terminal kinase domain (residues 784–1085), adopting a canonical kinase fold with two lobes. The [[Adenosine triphosphate|ATP]] binding and the catalytic sites are located at the interface of the two lobes. The N-terminal extension contains three [[beta sheet|β-strands]] and an [[alpha helix|α-helix]], wrapping around the N lobe of the kinase domain.<ref name="pmid18995837">{{PDB|3E7E}}; {{cite journal |vauthors=Kang J, Yang M, Li B, Qi W, Zhang C, Shokat KM, Tomchick DR, Machius M, Yu H | title = Structure and substrate recruitment of the human spindle checkpoint kinase Bub1 | journal = Mol. Cell | volume = 32 | issue = 3 | pages = 394–405 | date = November 2008 | pmid = 18995837 | pmc = 2644263 | doi = 10.1016/j.molcel.2008.09.017 }}</ref>{{rp|Figure1}}
== Subcellular location ==
In humans Bub1 accumulates gradually during [[G1 phase|G1]] and [[S phase|S]] phase of the [[cell cycle]], peaks at G2/M, and drops dramatically after mitosis. During [[prophase]] it localizes as one of the first proteins to the outer kinetochore, a process generally implicated in correct mitotic timing and checkpoint response to spindle damage.<ref>[[UniProt]]: {{UniProt|O43683}}</ref>
== Function ==
The protein kinase Bub1 possesses versatile and distinct functions during the cell cycle, mainly in the SAC and chromosome alignment during metaphase. The protein's interaction network currently identified is similarly complex (see Figure 1).
[[Image:Net image e kC3oSkmqG60N high res.png|thumb|Figure 1: Protein interaction network of human Bub1.<ref name="urlBUB1 protein (Homo sapiens) - STRING interaction network">{{cite web | url = http://string82.embl.de/newstring_cgi/show_network_section.pl?identifier=9606.ENSP00000302530&all_channels_on=1&interactive=yes&network_flavor=evidence&targetmode=proteins | title = BUB1 protein (Homo sapiens) - STRING interaction network | work = STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) | publisher = European Molecular Biology Laboratory | archive-url = https://web.archive.org/web/20110718234213/http://string82.embl.de/newstring_cgi/show_network_section.pl?identifier=9606.ENSP00000302530&all_channels_on=1&interactive=yes&network_flavor=evidence&targetmode=proteins | archive-date = 2011-07-18 | access-date = 2010-06-29 | url-status = dead }}</ref>]]
In eukaryotic cells the SAC serves as the central surveillance mechanism to ensure chromosomes are being passed on to the next generation in a reliable manner. Several components monitor correct bipolar attachment of microtubules to the kinetochore, presumably through detection of tension. Metaphase-to-[[anaphase]] transition is halted by the SAC as long as single kinetochores lack bipolar microtubule attachment, implying the need for a highly sensitive signaling pathway. Bub1 was claimed to be the master regulator of SAC formation and signaling. At least thirteen other proteins ([[Mad1]], [[MAD2]], [[BUB1B|MAD3]]/BubR1, [[BUB3]], [[RPS27|Mps1]] etc.) are part of the check point, among which many have been identified to interact with Bub1.
Upon activation of the SAC Bub1 directly phosphorylates [[Anaphase-promoting complex|APC]]/C's coactivator [[CDC20|Cdc20]].<ref name="pmid15525512">{{cite journal | vauthors = Tang Z, Shu H, Oncel D, Chen S, Yu H | title = Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint | journal = Molecular Cell | volume = 16 | issue = 3 | pages = 387–97 | date = Nov 2004 | pmid = 15525512 | doi = 10.1016/j.molcel.2004.09.031 | doi-access = free }}</ref> This phosphorylation event is probably achieved in complex with Bub3, which itself has been subjected to prior phosphorylation by Bub1. The phosphorylation of Cdc20 ultimately leads to decreased activity of APC/C which determines the metaphase-to-anaphase transition.  In turn APC/C, now in complex with Cdh1, also acts on Bub1 by priming it for degradation to exit mitosis.<ref name="pmid17158872">{{cite journal | vauthors = Qi W, Yu H | title = KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome | journal = The Journal of Biological Chemistry | volume = 282 | issue = 6 | pages = 3672–9 | date = Feb 2007 | pmid = 17158872 | doi = 10.1074/jbc.M609376200 | doi-access = free }}</ref>
In addition, kinetochore localization of Bub1 early during G2 or prophase is another aspect of SAC functioning. Bub1 is thought to serve as a platform recruiting other checkpoint and motor proteins as Mad1, Mad2, BubR1, CENP-E and [[PLK1]] to the kinetochore.<ref name="pmid11402067">{{cite journal | vauthors = Sharp-Baker H, Chen RH | title = Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity | journal = The Journal of Cell Biology | volume = 153 | issue = 6 | pages = 1239–50 | date = Jun 2001 | pmid = 11402067 | pmc = 2192030 | doi = 10.1083/jcb.153.6.1239 }}</ref><ref name="pmid15020684">{{cite journal | vauthors = Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS | title = Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression | journal = Journal of Cell Science | volume = 117 | issue = Pt 8 | pages = 1577–89 | date = Mar 2004 | pmid = 15020684 | doi = 10.1242/jcs.01006 | doi-access = free }}</ref><ref name="pmid15239953">{{cite journal | vauthors = Meraldi P, Draviam VM, Sorger PK | title = Timing and checkpoints in the regulation of mitotic progression | journal = Developmental Cell | volume = 7 | issue = 1 | pages = 45–60 | date = Jul 2004 | pmid = 15239953 | doi = 10.1016/j.devcel.2004.06.006 | doi-access = free }}</ref> Indeed, recent data suggest that the primary role of Bub1 during SAC activity is not Cdc20 phosphorylation but rather recruitment of BubR1, Mad1 and Mad2.<ref name="pmid19487456">{{cite journal | vauthors = Klebig C, Korinth D, Meraldi P | title = Bub1 regulates chromosome segregation in a kinetochore-independent manner | journal = The Journal of Cell Biology | volume = 185 | issue = 5 | pages = 841–58 | date = Jun 2009 | pmid = 19487456 | pmc = 2711590 | doi = 10.1083/jcb.200902128 }}</ref>
Upon spindle damage Bub1 is also triggered to phosphorylate Mad1<ref name="pmid12473343">{{cite journal | vauthors = Yu H | title = Regulation of APC-Cdc20 by the spindle checkpoint | journal = Current Opinion in Cell Biology | volume = 14 | issue = 6 | pages = 706–14 | date = Dec 2002 | pmid = 12473343 | doi = 10.1016/S0955-0674(02)00382-4 }}</ref><ref name="pmid11438673">{{cite journal | vauthors = Zhang Y, Lees E | title = Identification of an overlapping binding domain on Cdc20 for Mad2 and anaphase-promoting complex: model for spindle checkpoint regulation | journal = Molecular and Cellular Biology | volume = 21 | issue = 15 | pages = 5190–9 | date = Aug 2001 | pmid = 11438673 | pmc = 87243 | doi = 10.1128/MCB.21.15.5190-5199.2001 }}</ref> leading to dissociation of the Mad1-Mad2 complex and thereby rendering Mad2 accessible for inhibition of Cdc20.
Bub1 generally protects sister chromatide cohesion by enhancing Shugoshin protein ([[SGOL1|Sgo1]]) localization to the centromeric region. Through recruitment of the phosphatase [[PP2A]] Bub1 inhibits the action of PLK1, which removes Sgo1 from the centromere.<ref name="pmid15604152">{{cite journal | vauthors = Tang Z, Sun Y, Harley SE, Zou H, Yu H | title = Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 52 | pages = 18012–7 | date = Dec 2004 | pmid = 15604152 | pmc = 539817 | doi = 10.1073/pnas.0408600102 | bibcode = 2004PNAS..10118012T | doi-access = free }}</ref><ref name="pmid16580887">{{cite journal | vauthors = Tang Z, Shu H, Qi W, Mahmood NA, Mumby MC, Yu H | title = PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation | journal = Developmental Cell | volume = 10 | issue = 5 | pages = 575–85 | date = May 2006 | pmid = 16580887 | doi = 10.1016/j.devcel.2006.03.010 | doi-access = free }}</ref><ref name="pmid17121863">{{cite journal | vauthors = Jang YJ, Ji JH, Choi YC, Ryu CJ, Ko SY | title = Regulation of Polo-like kinase 1 by DNA damage in mitosis. Inhibition of mitotic PLK-1 by protein phosphatase 2A | journal = The Journal of Biological Chemistry | volume = 282 | issue = 4 | pages = 2473–82 | date = Jan 2007 | pmid = 17121863 | doi = 10.1074/jbc.M605480200 | doi-access = free }}</ref><ref name="pmid17617734">{{cite journal | vauthors = Pouwels J, Kukkonen AM, Lan W, Daum JR, Gorbsky GJ, Stukenberg T, Kallio MJ | title = Shugoshin 1 plays a central role in kinetochore assembly and is required for kinetochore targeting of Plk1 | journal = Cell Cycle | volume = 6 | issue = 13 | pages = 1579–85 | date = Jul 2007 | pmid = 17617734 | doi = 10.4161/cc.6.13.4442 | doi-access = free }}</ref>
Contrarily PLK1 localization, as mentioned, also depends on the activity of Bub1.   Studies in Xenopus extracts using RNAi or antibody depletion have indicated a crucial function of Bub1 in the organization of the inner centromere. Similarly to its role in kinetochore assembly, it recruits members of the chromosomal passenger complex (CPC) like [[Aurora B kinase]], [[Survivin]] and [[INCENP]]. Direct phosphorylation of  INCENP by Bub1 has been observed.<ref name="pmid17389228">{{cite journal | vauthors = Boyarchuk Y, Salic A, Dasso M, Arnaoutov A | title = Bub1 is essential for assembly of the functional inner centromere | journal = The Journal of Cell Biology | volume = 176 | issue = 7 | pages = 919–28 | date = Mar 2007 | pmid = 17389228 | pmc = 2064078 | doi = 10.1083/jcb.200609044 }}</ref>
RNAi mediated depletion of human Bub1 has indicated function in correct metaphase congression. Downstream targets identified are distinct kinetochore proteins as [[CENPF|CENP-F]], [[KIF2C|MCAK]] and the mentioned Sgo1.<ref name="pmid19487456" />
== Implications in cancer ==
Disturbed mitotic checkpoints are a common feature of many human cancers. More precisely, mutations in the spindle checkpoint can lead to chromosomal instability and aneuploidy, a feature present in over 90% of all solid tumors.<ref name="pmid19549887">{{cite journal | vauthors = Williams BR, Amon A | title = Aneuploidy: cancer's fatal flaw? | journal = Cancer Research | volume = 69 | issue = 13 | pages = 5289–91 | date = Jul 2009 | pmid = 19549887 | pmc = 2917070 | doi = 10.1158/0008-5472.CAN-09-0944 }}</ref>  Loss-of-function mutations or reduced gene expression of Bub1 have been identified in several human tumors as colon, esophageal, gastric, breast cancer and melanoma.<ref name="pmid19487456" /> A correlation between Bub1 expression levels and the localization of tumors along with their severity was found. For instance, low Bub1 expression levels resulted in more sarcomas, lymphomas and lung tumors, whereas higher ones caused sarcomas and tumors in the liver.<ref name="pmid18703117">{{cite journal | vauthors = King RW | title = When 2+2=5: the origins and fates of aneuploid and tetraploid cells |journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer| volume = 1786 | issue = 1 | pages = 4–14 | date = Sep 2008 | pmid = 18703117 | pmc = 2581926 | doi = 10.1016/j.bbcan.2008.07.007 }}</ref> Moreover, Bub1 has been identified as a target of the large T antigen of the SV-40 virus, possibly contributing to its potential for oncogenic transformation.<ref name="pmid18922873">{{cite journal | vauthors = Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV | title = Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding | journal = Journal of Virology | volume = 83 | issue = 1 | pages = 117–27 | date = Jan 2009 | pmid = 18922873 | pmc = 2612341 | doi = 10.1128/JVI.01515-08 }}</ref>
Indications for possible Bub1 involvement in [[tumorigenesis]] also derive from animal experiments, where mice with reduced Bub1 expression showed an increase in tumor susceptibility.<ref name="pmid17938250">{{cite journal | vauthors = Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM | title = Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis | journal = The Journal of Cell Biology | volume = 179 | issue = 2 | pages = 255–67 | date = Oct 2007 | pmid = 17938250 | pmc = 2064762 | doi = 10.1083/jcb.200706015 }}</ref><ref name="pmid19117986">{{cite journal | vauthors = Schliekelman M, Cowley DO, O'Quinn R, Oliver TG, Lu L, Salmon ED, Van Dyke T | title = Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis | journal = Cancer Research | volume = 69 | issue = 1 | pages = 45–54 | date = Jan 2009 | pmid = 19117986 | doi = 10.1158/0008-5472.CAN-07-6330 | pmc = 4770788 }}</ref> In vitro knockdown of Bub1 in [[p53]] impaired cells (e.g. HeLa cells) caused aneuploidy.<ref name="pmid17643075">{{cite journal | vauthors = Williams GL, Roberts TM, Gjoerup OV | title = Bub1: escapades in a cellular world | journal = Cell Cycle | volume = 6 | issue = 14 | pages = 1699–704 | date = Jul 2007 | pmid = 17643075 | doi = 10.4161/cc.6.14.4493 | doi-access = free }}</ref> Whether aneuploidy alone is a sufficient driving cause during tumorigenesis or rather a mere consequence has been a matter of scientific debate.
== Link to caspase-independent mitotic death (CIMD) ==
Recently Bub1 has been identified as a negative regulator of CIMD. Depletion of Bub1 results in increased CIMD in order to avoid aneuploidy caused by reduced SAC functioning. The transcriptional activity of [[p73]] is thereby inhibited via phosphorylation. Direct interaction between these two players has not been visualized so far, therefore molecules linking Bub1 and p73 are yet to be determined.<ref name="pmid18414023">{{cite journal | vauthors = Kitagawa K, Niikura Y | title = Caspase-independent mitotic death (CIMD) | journal = Cell Cycle | volume = 7 | issue = 8 | pages = 1001–5 | date = Apr 2008 | pmid = 18414023 | doi = 10.4161/cc.7.8.5720 | doi-access = free }}</ref>
It has also been proposed that Bub1 binds p53 to prevent it from activating pro-apoptotic genes, therefore p53 is able to induce [[apoptosis]] when Bub1 is depleted. However, an interaction between p53 and Bub1 has not yet been shown while p53 binding BubR1 has been reported.<ref name="pmid19270499">{{cite journal | vauthors = Beeharry N, Yen TJ | title = p53-dependent apoptosis in response to spindle damage is linked to loss of Bub1 | journal = Cancer Biology & Therapy | volume = 8 | issue = 7 | pages = 645–7 | date = Apr 2009 | pmid = 19270499 | doi = 10.4161/cbt.8.7.8140 | doi-access = free }}</ref>
== See also ==
*[[Mitosis]]
*[[Cell Cycle]]
== References ==
{{Reflist|35em}}
==External links==
* {{UCSC gene info|BUB1}}