Affinage

BUB1

Mitotic checkpoint serine/threonine-protein kinase BUB1 · UniProt O43683

Length
1085 aa
Mass
122.4 kDa
Annotated
2026-04-28
100 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BUB1 is a conserved serine/threonine kinase that functions as a central kinetochore scaffold and catalytic hub coordinating spindle assembly checkpoint (SAC) signaling, chromosome biorientation, and centromeric cohesion protection during cell division. BUB1 is recruited to kinetochores via its N-terminal TPR domain binding Mps1-phosphorylated MELT motifs on KNL1/Spc105, where it scaffolds recruitment of BubR1, RZZ, and Mad1–Mad2 through distinct domains, and positions Cdc20 on Mad1 to catalyze mitotic checkpoint complex (MCC) assembly (PMID:25611342, PMID:36289199, PMID:22521787). Its kinase activity phosphorylates histone H2A at T120/S121 to recruit shugoshin proteins for centromeric cohesion protection and to localize Aurora B for error correction of kinetochore–microtubule attachments, while it also directly and indirectly (via Plk1 scaffolding) phosphorylates Cdc20 to inhibit APC/C (PMID:19965387, PMID:15525512, PMID:26912231, PMID:23209306). Beyond mitosis, BUB1 promotes TGF-β receptor signaling by facilitating receptor heterodimerization and SMAD phosphorylation, and supports telomere replication by phosphorylating TRF1 downstream of TRF2-dependent recruitment (PMID:25564677, PMID:29727616).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Establishing BUB1 as a kinetochore-localized kinase required for the spindle assembly checkpoint answered the foundational question of whether vertebrate cells use checkpoint kinases analogous to yeast Bub1.

    Evidence Dominant-negative mutant expression and immunofluorescence in mammalian cells

    PMID:9182760

    Open questions at the time
    • Endogenous substrates unknown
    • Mechanism of kinetochore recruitment undefined
    • Relationship to BubR1 not established
  2. 1998 High

    Localization studies resolved when and where BUB1 acts: it arrives at outer kinetochores in early prophase before BubR1, and in fission yeast is essential for both checkpoint response and accurate chromosome segregation in unperturbed mitosis.

    Evidence Immunoelectron microscopy in human cells; gene deletion in fission yeast with live imaging

    PMID:9864354 PMID:9914370

    Open questions at the time
    • Mechanism of kinetochore targeting still unknown
    • No structural information on BUB1 domains
  3. 2001 High

    Multiple studies established that BUB1 has functions beyond checkpoint signaling: it is required for meiotic sister kinetochore co-orientation and centromeric cohesion protection in fission yeast, and is activated by the MAPK/p90Rsk pathway during meiosis.

    Evidence Gene deletion in fission yeast meiosis; kinase assays and MEK inhibition in Xenopus oocytes

    PMID:11231148 PMID:11274370 PMID:11331883

    Open questions at the time
    • Substrate linking BUB1 to cohesion protection not identified
    • Mechanism of MAPK-mediated activation unclear structurally
  4. 2004 High

    Identification of Cdc20 as a direct BUB1 kinase substrate explained how BUB1 catalytic activity inhibits APC/C: phosphorylation of six Cdc20 sites blocks APC/C activation, and non-phosphorylatable Cdc20 permits mitotic exit despite spindle damage.

    Evidence In vitro kinase and APC/C ubiquitination assays with site-directed mutagenesis; RNAi in HeLa cells

    PMID:15525512

    Open questions at the time
    • Whether Cdc20 phosphorylation is sufficient for checkpoint in vivo uncertain
    • Other catalytic substrates not yet identified
  5. 2005 High

    Discovery that BUB1 is required for centromeric localization of shugoshin (Sgo1) and for accurate bipolar kinetochore–microtubule attachment linked BUB1 to cohesion protection and error correction pathways distinct from its checkpoint role.

    Evidence RNAi in human cells with localization and cohesion phenotypes; epistasis with Aurora B

    PMID:15723797 PMID:15933723

    Open questions at the time
    • Direct BUB1 substrate mediating Sgo1 recruitment unknown
    • Mechanism of parallel action with Aurora B not resolved
  6. 2006 High

    BUB1 was shown to recruit Plk1 to kinetochores via Cdk1-phosphorylated T609, and to be degraded by APC/C(Cdh1) through KEN-box motifs, establishing BUB1 as both a scaffold for Plk1 and a regulated APC/C substrate.

    Evidence Reciprocal Co-IP with T609A mutagenesis; in vitro ubiquitination by APC/C(Cdh1) with KEN-box mutagenesis

    PMID:16760428 PMID:17158872

    Open questions at the time
    • Functional consequence of Plk1 recruitment via BUB1 not yet defined
    • How KEN boxes coordinate Cdc20 binding vs. APC/C-mediated degradation unclear
  7. 2008 High

    Crystal structure of the BUB1 kinase domain revealed an N-terminal extension required for activity and showed that BUB1 uses KEN-box motifs to dock Cdc20 for checkpoint signaling, resolving how a single kinase accomplishes both catalytic and scaffolding functions.

    Evidence X-ray crystallography with mutagenesis and checkpoint assay in HeLa cells

    PMID:18995837

    Open questions at the time
    • Substrate selectivity mechanism not resolved
    • How kinase domain activation segment restricts access unknown
  8. 2009 High

    Identification of histone H2A S121 (T120 in mammals) as the direct BUB1 kinase substrate responsible for shugoshin recruitment answered a long-standing question about the molecular mechanism connecting BUB1 kinase activity to cohesion protection.

    Evidence In vitro kinase assay, h2a-SA mutagenesis phenocopying bub1-KD, ectopic tethering rescue in fission yeast

    PMID:19965387

    Open questions at the time
    • Structural basis of H2A recognition by BUB1 unknown
    • Whether this mechanism is fully conserved in mammals not yet confirmed
  9. 2009 High

    The crystal structure of BUB1's TPR domain and its interaction with KNL1 defined the structural basis of BUB1 kinetochore recruitment, answering how BUB1 docks at unattached kinetochores.

    Evidence X-ray crystallography at 1.74 Å with functional mutagenesis and localization assay

    PMID:19141287

    Open questions at the time
    • How phospho-MELT recognition integrates with TPR–KI interaction not yet clear
  10. 2012 High

    Parallel studies in budding and fission yeast established that Mps1 phosphorylation of MELT motifs on KNL1/Spc105 is the signal that recruits BUB1–BUB3, explaining the upstream regulation of BUB1 kinetochore targeting and linking it to unattached kinetochore status.

    Evidence Kinetochore particle purification, in vitro kinase assay, phosphosite mutagenesis in S. cerevisiae and S. pombe

    PMID:22521786 PMID:22521787

    Open questions at the time
    • Valency and cooperativity of multi-MELT engagement not yet quantified
    • PP1 reversal kinetics not defined
  11. 2012 High

    A kinase-dead knockin mouse demonstrated that BUB1 kinase activity drives H2A-T121 phosphorylation, Aurora B centromeric localization, and error correction in vivo, but is dispensable for tumor suppression, separating catalytic from scaffolding functions in a mammalian organism.

    Evidence Knockin mouse model with H2A-T121 phosphorylation and Aurora B localization assays

    PMID:23209306

    Open questions at the time
    • Why kinase-dead mice lack tumor susceptibility despite segregation errors is unexplained
    • Contribution of scaffolding vs. kinase to SAC not fully delineated in vivo
  12. 2015 High

    Domain mapping in human BUB1 resolved how a single scaffold protein recruits distinct checkpoint effectors: separate domains mediate BubR1 heterodimerization, RZZ recruitment, and Cdc20 binding (via ABBA motif and KEN box), while BUB1 enhances BUB3 phospho-MELT binding to explain why BubR1 depends on BUB1 for kinetochore access.

    Evidence Structural analysis, domain deletion, chimeric constructs, checkpoint and localization assays

    PMID:25611342 PMID:26031201 PMID:26148513

    Open questions at the time
    • How removal of BubR1-recruiting domain increases checkpoint strength is paradoxical and unexplained
    • Stoichiometry of BUB1 scaffold complexes at kinetochores undefined
  13. 2015 High

    Discovery that BUB1 promotes TGF-β signaling by forming a ternary complex with TGF-β receptors and facilitating SMAD phosphorylation established a non-mitotic function for BUB1 kinase activity in a major signaling pathway.

    Evidence RNAi kinome screen, Co-IP, kinase-dead mutant, small-molecule inhibitor, xenograft model

    PMID:25564677

    Open questions at the time
    • Direct BUB1 phosphorylation target in TGF-β pathway not identified
    • How cytoplasmic TGF-β signaling interfaces with kinetochore BUB1 pool unclear
  14. 2016 High

    Selective BUB1 kinase inhibitors (BAY-320/BAY-524) confirmed that catalytic activity is specifically required for shugoshin and Aurora B chromosomal localization but has only minor effects on SAC function, definitively separating kinase-dependent from scaffold-dependent roles.

    Evidence Small-molecule kinase inhibitors with immunofluorescence, mitotic timing, and drug combination assays

    PMID:26885717

    Open questions at the time
    • Whether kinase inhibition sensitizes tumors to taxanes in patients untested
    • Off-target effects not fully excluded
  15. 2016 High

    BUB1 was shown to scaffold Plk1-mediated phosphorylation of Cdc20 as a parallel APC/C inhibitory mechanism alongside MCC formation, resolving the functional consequence of the BUB1-Plk1 interaction discovered a decade earlier.

    Evidence In vitro APC/C assay, RNAi, phospho-mimetic Cdc20 rescue of Mad2/BubR1-depleted cells

    PMID:26912231

    Open questions at the time
    • Relative contribution of direct BUB1 vs. BUB1-scaffolded Plk1 phosphorylation of Cdc20 not quantified in vivo
  16. 2018 High

    BUB1–BUB3 was found to localize to telomeres during S phase via TRF2 and phosphorylate TRF1 to recruit BLM helicase for replication stress resolution, establishing a replication function entirely outside mitosis.

    Evidence Co-IP, in vitro kinase assay, chromatin fractionation, telomere replication assay

    PMID:29727616

    Open questions at the time
    • BUB1 phosphosite(s) on TRF1 not mapped
    • Whether telomere shortening phenotype is kinase-dependent not fully tested
  17. 2020 High

    Combined inhibition of BUB1 and Haspin fully abolished centromeric Aurora B accumulation, demonstrating that two parallel histone-mark pathways converge to position the chromosomal passenger complex for error correction.

    Evidence Single and combined kinase inhibition with immunofluorescence and segregation assays

    PMID:32027339

    Open questions at the time
    • Whether Aurora B at other loci compensates for centromeric loss not fully resolved
    • Quantitative contribution of each pathway varies by cell type
  18. 2022 High

    Structural reconstitution of the Mps1-phosphorylated Bub1–Cdc20–Mad1 CTD tripartite complex explained the catalytic mechanism of MCC assembly: Bub1 and Cdc20 are co-positioned on Mad1 to present Cdc20's Mad2-interacting motif near open-Mad2, resolving the long-sought template model for checkpoint signal generation.

    Evidence X-ray crystallography, cross-linking mass spectrometry, in vitro MCC reconstitution

    PMID:36289199

    Open questions at the time
    • How kinetochore geometry and valency modulate catalytic rate not determined
    • Full-length reconstitution of the signaling cascade from Mps1 through MCC not achieved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how BUB1's mitotic and interphase pools are differentially regulated, the structural basis for substrate selectivity between H2A and Cdc20, quantitative contributions of BUB1's scaffold versus kinase activities to SAC robustness in human tissues, and whether BUB1 kinase inhibition has therapeutic utility.
  • No full-length BUB1 structure
  • No in vivo quantitative model integrating all BUB1 activities
  • Therapeutic window for BUB1 kinase inhibition not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0060090 molecular adaptor activity 4 GO:0042393 histone binding 3
Localization
GO:0005694 chromosome 6 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-4839726 Chromatin organization 3 R-HSA-162582 Signal Transduction 1 R-HSA-69306 DNA Replication 1
Partners
BUB3BUBR1CDC20KNL1MAD1PLK1SGO1TRF2
Complex memberships
BUB1–BUB3MCC (mitotic checkpoint complex)

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Murine Bub1 localizes to the kinetochore during mitosis, and expression of a dominant-negative mutant shows Bub1 is required for both the spindle checkpoint response to spindle damage and for normal mitotic timing. Dominant-negative mutant expression, immunofluorescence localization Cell High 9182760
1998 hBUB1 first appears at kinetochores during early prophase before hBUBR1; both kinases concentrate at the outer kinetochore plate and co-localize with CENP-E, suggesting they monitor kinetochore-microtubule interactions. Immunofluorescence, immunoelectron microscopy, antibody localization Chromosoma High 9914370
1998 Fission yeast Bub1 is recruited to centromeres upon spindle checkpoint activation and is essential for the checkpoint response to spindle damage and centromere defects; loss of bub1 causes chromosome lagging and increased chromosome loss in unperturbed mitosis. Gene deletion, immunofluorescence, live imaging The Journal of cell biology High 9864354
1999 BUB1 and BUB3 form a complex of monomers that interacts with MAD1; this multiprotein complex exhibits kinase activity requiring Lys821 in the BUB1 kinase motif, resulting in BUB1 autophosphorylation and phosphorylation of associated MAD1. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis Biochemical and biophysical research communications Medium 10198256
2001 Bub1 localizes to kinetochores during meiosis I and II in Xenopus oocytes; its electrophoretic mobility shifts (reflecting phosphorylation and activation) during meiosis I, and this activation is MAPK-dependent and can be induced by p90(Rsk), which phosphorylates Bub1 in vitro and increases its kinase activity. In vitro kinase assay, immunofluorescence, MEK inhibitor (U0126), injection of constitutively active p90Rsk Current biology : CB High 11231148
2001 In mammalian cells, Bub1 and BubR1 are recruited to kinetochores in response to loss of tension (low-dose vinblastine) but not microtubule detachment, while Mad2 responds to attachment loss; Mad2 does not associate with Bub1 or BubR1, indicating they operate in distinct checkpoint pathways. Immunofluorescence with microtubule toxins at defined doses, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 11274370
2001 Bub1 and BubR1 are part of a common complex during mitosis; Bub1 localization is sensitive to both tension and microtubule attachment (asymmetric at kinetochores, dependent on microtubule attachment), while BubR1 localization is symmetrical; Bub1 is rapidly phosphorylated by nocodazole or taxol treatment. Immunofluorescence, cell synchronization, microtubule toxin treatment Journal of cell science Medium 11792804
2001 Fission yeast Bub1 is essential for the meiotic pattern of chromosome segregation: Bub1 deletion causes sister kinetochores to disunite at MI and prevents retention of Rec8 cohesin at centromeres at anaphase I, revealing roles in sister kinetochore co-orientation and centromeric cohesion beyond spindle checkpoint. Gene deletion, live imaging, immunofluorescence Nature cell biology High 11331883
2002 Immunodepletion of Bub1 from Xenopus egg extracts blocks Mos-dependent establishment of CSF arrest; rescue requires wild-type but not kinase-dead Bub1, demonstrating that Bub1 kinase activity is required for establishment of meiotic metaphase arrest and APC inhibition downstream of MAPK/Rsk. Immunodepletion from egg extracts, kinase-dead rescue, in vitro reconstitution Current biology : CB High 12123578
2004 Bub1 directly phosphorylates Cdc20 in vitro and catalytically inhibits APC/C(Cdc20) ubiquitin ligase activity; a Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to inhibition; upon checkpoint activation, Bub1 kinase activity toward Cdc20 is stimulated; expression of non-phosphorylatable Cdc20 allows mitotic exit despite spindle damage. In vitro kinase assay, site-directed mutagenesis, APC/C ubiquitination assay, RNAi in HeLa cells Molecular cell High 15525512
2004 Xenopus Bub1 is hyperphosphorylated and activated on unattached chromosomes; MAPK phosphorylates Bub1 at consensus sites and is required for this activation; activated Bub1 enhances checkpoint efficiency and promotes recruitment of other checkpoint proteins to kinetochores. In vitro kinase assay, MAPK inhibition, site-directed mutagenesis, checkpoint assay in Xenopus The EMBO journal High 15241477
2005 Human Bub1 is required for centromeric localization of Sgo1 (shugoshin) during mitosis; Bub1 depletion causes Sgo1 to redistribute along chromosome arms and leads to loosening of centromeric cohesion. RNAi knockdown, immunofluorescence, live-cell imaging Current biology : CB High 15723797
2005 Bub1 depletion leads to accumulation of misaligned chromatids with both sister kinetochores linked to microtubules abnormally; Bub1 and Aurora B are recruited to kinetochores independently of each other and have additive effects when co-depleted, indicating parallel pathways for stable bipolar kinetochore-microtubule attachment. RNAi, live-cell imaging, fluorescence microscopy, double-depletion epistasis The EMBO journal High 15933723
2006 Plk1 binds Bub1 through its polo-box domain (PBD) in mitotic cells; this interaction requires Cdk1-mediated phosphorylation of Bub1 at T609; Bub1 depletion diminishes kinetochore localization of Plk1, and expression of wild-type but not T609A Bub1 restores Plk1 kinetochore localization. Co-immunoprecipitation, site-directed mutagenesis, RNAi, immunofluorescence, in vitro kinase assay Molecular biology of the cell High 16760428
2006 Bub1 is degraded during mitotic exit by APC/C(Cdh1) through two KEN-box motifs; mutation of both KEN boxes stabilizes Bub1 in cells; Bub1 is ubiquitinated by immunopurified APC/C(Cdh1) in vitro. In vitro ubiquitination assay, site-directed mutagenesis, RNAi of Cdh1, protein stability assay The Journal of biological chemistry High 17158872
2007 Budding yeast Bub1 kinase domain is required for accurate chromosome biorientation after nocodazole release; Bub1 kinase mislocalizes Sgo1p when absent, and both kinase domain and Sgo1 are required for efficient biorientation. Kinase-domain deletion, live imaging, immunofluorescence, genetic epistasis PLoS genetics High 18081426
2007 In fission yeast, Bub1 acts as a stable kinetochore scaffold (confirmed by FRAP); tethering Bub1 to telomeres is sufficient to recruit anaphase inhibitors (Mad2, Mad3) in a kinase-independent manner. FRAP, ectopic tethering to telomeres, kinetochore recruitment assay PloS one High 18094750
2007 BUB1 depletion in normal human fibroblasts via RNAi triggers premature senescence dependent on p53 and its target p21(CIP1); cells with reduced Bub1 and inactivated p53 become highly aneuploid, revealing a surveillance mechanism linking Bub1 loss to the p53 pathway. RNAi knockdown, dominant-negative p53, p21 depletion, senescence assay Proceedings of the National Academy of Sciences of the United States of America High 17488820
2008 Crystal structure of the Bub1 kinase domain reveals an N-terminal extension required for kinase activity; the activation segment has active-kinase features but its C-terminal portion sterically restricts substrate access; Bub1 uses KEN-box docking motifs outside the kinase domain to recruit Cdc20, and these KEN boxes are required for spindle checkpoint function in human cells. X-ray crystallography, mutagenesis, in vitro kinase assay, checkpoint assay in HeLa cells Molecular cell High 18995837
2008 SV40 large T antigen binds Bub1 directly; T antigen coimmunoprecipitates with endogenous Bub1 and Bub3; spindle checkpoint override by T antigen depends on Bub1 binding, and T antigen-induced tetraploidy and DNA damage response (p53 stabilization via ATM/ATR) are also Bub1-binding dependent. Co-immunoprecipitation, genetic analysis (T antigen mutants), DNA damage markers Journal of virology Medium 18922873
2009 Bub1 phosphorylates the conserved serine 121 of histone H2A in fission yeast; this phosphorylation is required for centromeric localization of shugoshin proteins; h2a-SA mutant phenocopies bub1 kinase-dead mutant; artificial tethering of shugoshin to centromeres rescues CIN defects in both h2a-SA and bub1-KD mutants. In vitro kinase assay, site-directed mutagenesis, ectopic tethering rescue, genetic epistasis Science (New York, N.Y.) High 19965387
2009 Crystal structure of the N-terminal TPR region of BUB1 at 1.74 Å resolution; functional mutagenesis identifies residues important for interaction with the kinetochore protein Blinkin (KNL1), which is required for kinetochore localization and function of BUB1 in the SAC. X-ray crystallography, site-directed mutagenesis, in vivo localization assay Structure (London, England : 1993) High 19141287
2009 In oocytes, Bub1 controls APC/C activation timing: Bub1 deletion accelerates APC/C-mediated securin destruction by ~5 hours; Bub1's kinase domain is not required for this APC/C delay; premature chiasmata resolution in Bub1-deficient oocytes requires APC/C and separase activity. Cre-lox conditional oocyte knockout, quantitative APC/C activity assay, genetic epistasis with Apc2 and separase Current biology : CB High 19249208
2010 Sgo1 is first recruited to centromeric heterochromatin in G2 in an HP1-dependent but Bub1-kinase-independent manner; during prophase, Sgo1 centromeric re-localization requires Bub1 kinase activity; Bub1 kinase activity is not required for checkpoint function or chromosome alignment in mammalian cells using BUB1-null MEF complementation. Null MEF complementation with kinase-dead Bub1, live-cell imaging, immunofluorescence across cell cycle stages Journal of cell science High 20124418
2011 Bub1 overexpression in mice causes aberrant kinase activity and hyperactivation of Aurora B kinase, leading to chromosome misalignment/lagging and aneuploidy; pharmacological or genetic (BubR1 overexpression) suppression of Aurora B corrects these errors, placing Aurora B downstream of Bub1 overexpression. Transgenic mouse overexpression, Aurora B inhibition, epistasis by BubR1 overexpression, live imaging The Journal of cell biology High 21646403
2012 Mps1 is the major kinase copurifying with yeast kinetochore particles and phosphorylates conserved MELT motifs in Spc105/KNL1; this phosphorylation recruits Bub1 to kinetochores and is reversed by PP1; Spc105 mutants lacking MELT phosphorylation sites are checkpoint-defective. Kinetochore particle purification, in vitro kinase assay, phosphosite mutagenesis, checkpoint assay Current biology : CB High 22521787
2012 Mps1 (Mph1) phosphorylation of MELT motifs in Spc7 (KNL1 ortholog) recruits Bub1 and Bub3 to kinetochores in fission yeast, and this recruitment is required to maintain SAC signaling. Phosphosite mutagenesis, kinetochore recruitment assay, checkpoint assay Current biology : CB High 22521786
2012 Crystal structure of Bub1 TPR domain in complex with KNL1 KI motif; interaction occurs along the convex TPR surface; point mutations on this surface impair Bub1-KNL1 interaction in vitro and in vivo; a 62-residue segment C-terminal to the TPRs including the Bub3-binding domain is necessary and largely sufficient for kinetochore recruitment. X-ray crystallography, site-directed mutagenesis, in vitro binding, in vivo kinetochore localization assay The Journal of cell biology High 22331848
2012 Bub1 kinase activity drives error correction and mitotic checkpoint signaling in mice via phosphorylation of histone H2A at T121, which controls Aurora B kinase localization and activity; mice lacking Bub1 kinase activity show substantial chromosome segregation errors but no increased tumor susceptibility. Knockin mouse (kinase-dead), H2A-T121 phosphorylation assay, Aurora B localization, tumor analysis The Journal of cell biology High 23209306
2014 Mad1 kinetochore localization in budding yeast is mediated by Mps1 phosphorylation of a conserved region within Bub1; tethering this Bub1 region to kinetochores bypasses the need for upstream checkpoint recruitment of Mps1; the Mad1 interaction with Bub1 and kinetochores can be reconstituted with Mps1 and Mad2 in vitro. Reconstitution in vitro, kinetochore tethering bypass, checkpoint genetics Genes & development High 24402315
2014 Phosphorylation at the P+1 loop of human Bub1 enhances its activity specifically toward H2A but not Cdc20; crystal structure of phosphorylated Bub1 reveals phosphorylation-triggered reorganization of the P+1 loop; this activating phosphorylation occurs constitutively during the cell cycle and appears to be intramolecular autophosphorylation; enrichment of H2A-pT120 at mitotic kinetochores requires kinetochore targeting of Bub1. X-ray crystallography, in vitro kinase assay, substrate-specific phosphorylation, mutagenesis Structure (London, England : 1993) High 25308863
2014 BuGZ binds and stabilizes Bub3 during interphase and mitosis through its GLEBS domain; BuGZ inhibition causes loss of both Bub3 and Bub1 from kinetochores, reduction of Bub1-dependent H2A phosphorylation at centromeres, and attenuation of Aurora B activity, leading to chromosome congression defects. RNAi, co-immunoprecipitation, immunofluorescence, phosphorylation assay Developmental cell High 24462187
2015 Bub1 and BubR1 heterodimerize with each other at a pseudo-symmetric interface; Bub1 (but not BubR1) enhances Bub3 binding to phosphorylated kinetochores; grafting a short Bub1 motif onto BubR1 promotes Bub1-independent kinetochore recruitment of BubR1 but cannot sustain a functional checkpoint; kinetochore localization of BubR1 requires direct heterodimerization with Bub1. Structural analysis, in vitro binding, mutagenesis, gain-of-function chimera, checkpoint assay eLife High 25611342
2015 Bub1 kinase activity promotes TGF-β signaling: Bub1 interacts with TGFBRI and TGFBRII forming a ternary complex, promotes receptor heterodimerization, and is required for SMAD3 recruitment, SMAD2/3 phosphorylation, and SMAD-dependent transcription; a kinase-dead Bub1 mutant and small-molecule inhibitor (2OH-BNPP1) suppress TGF-β signaling. RNAi kinome screen, co-immunoprecipitation, kinase-dead mutant, small-molecule inhibitor, in vivo xenograft Science signaling High 25564677
2015 Human BUB1 contributes to SAC signaling through a 50-amino-acid segment containing an ABBA motif and KEN box that promotes efficient CDC20 binding at kinetochores; kinetochore recruitment of BUBR1 and BUB3 by BUB1 is dispensable for SAC activation; human BUB1 does not stably associate with MAD1. Domain deletion/mutagenesis, complementation, checkpoint assay, Co-IP Journal of cell science High 26148513
2015 Distinct domains within Bub1 mediate kinetochore recruitment of RZZ complex and BubR1 separately; the middle region of Bub1 contributes to RZZ localization; a distinct region mediates BubR1 kinetochore localization through direct binding; removal of the BubR1-recruiting region paradoxically increases checkpoint strength. Domain deletion, Co-IP, immunofluorescence, checkpoint assay Nature communications High 26031201
2015 Bub1 autophosphorylation at T589 controls kinetochore turnover of Bub1; T589A mutation causes uniform H2A-T120 phosphorylation along chromosome arms and aberrant Sgo1 recruitment; kinetochore tethering of Bub1-T589A refocuses H2A-T120 phosphorylation to centromeres, linking Bub1 kinetochore docking to localized H2A phosphorylation. Quantitative phosphoproteomics, autophosphorylation assay, site-directed mutagenesis, kinetochore tethering Nature communications High 26399325
2016 Bub1 inhibition (BAY-320 and BAY-524) reduces shugoshin and chromosomal passenger complex (CPC/Aurora B) chromosomal association, impairs chromosome arm resolution, and sensitizes cells to paclitaxel; Bub1 inhibition has only minor effects on mitotic progression or SAC function, distinguishing scaffolding from catalytic roles. Small-molecule kinase inhibitors (BAY-320, BAY-524), immunofluorescence, mitotic timing assay, drug combination assay eLife High 26885717
2016 Bub1 scaffolds Plk1-mediated phosphorylation of Cdc20; Bub1-Plk1-dependent Cdc20 phosphorylation inhibits APC/C(Cdc20) in vitro, is required for checkpoint signaling in human cells, and acts in a parallel pathway to MCC formation; a phospho-mimicking Cdc20 mutant restores mitotic arrest in Mad2 or BubR1-depleted cells. In vitro APC/C assay, Co-IP, RNAi, phospho-mimetic rescue, checkpoint assay Nature communications High 26912231
2016 In fission yeast, multisite binding of Bub3 to the Spc7 MELT array toggles the spindle checkpoint switch by permitting Mph1 (Mps1)-dependent interaction of Bub1 with Mad1-Mad2. Phosphosite mutagenesis, checkpoint functional assay, Co-IP Current biology : CB Medium 27618268
2017 In fission yeast meiosis, Moa1 (meikin) recruits Plo1 (polo-like kinase) to kinetochores to phosphorylate Spc7 (KNL1) and accumulate Bub1, causing meiotic Bub1 to persist at kinetochores until anaphase I; this ensures robust Sgo1 localization and centromeric cohesion protection; this meiosis-specific Bub1 regulation is conserved in mouse. Genetic analysis, immunofluorescence, kinase assay, mouse meiosis analysis Genes to cells : devoted to molecular & cellular mechanisms Medium 28497540
2018 The BUB3-BUB1 complex binds to telomeres during S phase and promotes telomere DNA replication; loss of the complex causes fragile and shortened telomeres; TRF2 targets BUB1-BUB3 to telomeres; BUB1 directly phosphorylates TRF1 to promote recruitment of BLM helicase for resolution of replication stress. Co-immunoprecipitation, in vitro kinase assay, chromatin fractionation, telomere replication assay Molecular cell High 29727616
2018 Malonylation of histone H2A at K119 inhibits the interaction between Bub1 and H2A, reducing Bub1-dependent H2A-S121 phosphorylation in vitro and causing loss of shugoshin chromosomal localization; anionic mutations at K119 phenocopy this in yeast. In vitro peptide binding assay, in vitro kinase assay, site-directed mutagenesis Scientific reports Medium 29769606
2018 In human cells, RZZ's sole role in SAC activation is to tether Mad1-Mad2 to kinetochores; Bub1 and KNL1 activate kinetochore-bound Mad1-Mad2 to produce a 'wait anaphase' signal but are not required for fibrous corona formation; Mps1 phosphorylates Rod to trigger corona formation independently of Bub1. Genome editing (BUB1 disruption), RNAi, checkpoint assay, immunofluorescence Current biology : CB High 30415700
2019 Efficient spindle checkpoint signaling requires integrated activities of Bub1 and the RZZ complex; Rod removal reduces proximity of Bub1 and Mad1; bypassing Rod requirement by tethering Mad1 or strengthening Bub1-Mad1 interaction is sufficient; Bub1 has checkpoint functions independent of Mad1 localization, suggesting a catalytic role. Genome editing + RNAi, proximity ligation assay, tethering bypass, checkpoint assay The EMBO journal High 30782962
2020 Either Haspin or Bub1 activity is sufficient to recruit Aurora B to distinct chromosomal loci; joint inhibition of both kinases fully abolishes Aurora B accumulation at centromeres, impairing correction of erroneous KT-MT attachments; Aurora B substrates at the kinetochore (Hec1, Dsn1, Knl1) are phosphorylated independently of centromere-localized Aurora B pools. Kinase inhibition (single and combined), immunofluorescence, chromosome segregation assay The Journal of cell biology High 32027339
2021 Aurora B kinase directly promotes MCC production by working downstream of Mps1 in budding yeast and human cells; conditional dimerization of Aurora B with Bub1 (but not with the Spc105 phosphodomain) leads to ectopic MCC production; Bub1 must recruit both Mad1 and Cdc20 for this signaling; Aurora B cooperates with Bub1 after Mps1 licenses Bub1 recruitment. Ectopic SAC activation (eSAC) system, conditional dimerization, checkpoint assay in yeast and HeLa cells Current biology : CB High 34861183
2021 BUB1 directly interacts with STAT3 and mediates phosphorylation of STAT3 at Ser727; pharmacological inhibition of BUB1 kinase activity or BUB1 kinase-domain mutation abrogates STAT3 transcriptional activation; BUB1 kinase inhibition suppresses bladder cancer cell growth in vitro and in vivo. Co-immunoprecipitation, in vitro kinase assay, kinase-dead mutant, pharmacological inhibitor, xenograft Journal of experimental & clinical cancer research : CR Medium 34852826
2021 Crystal structure of Mad1 C-terminal domain bound to two phosphorylated Bub1 CD1 peptides at 1.75 Å; phosphorylated Bub1 Thr461 interacts with Arg617 of the Mad1 RLK motif and acts as N-terminal cap to the CD1 α-helix dipole; only one Bub1 CD1 peptide binds the Mad1 homodimer in solution due to inherent asymmetry in the Mad1 coiled-coil. X-ray crystallography, NMR, solution binding assay EMBO reports High 34013668
2022 Mps1 phosphorylation of both Bub1 CD1 and Mad1 CTD generates a tripartite assembly of Bub1 and Cdc20 on Mad1 CTD; this positions Cdc20's Mad2-interacting motif (MIM) near open-Mad2 to catalyze C-Mad2:Cdc20 formation and MCC assembly. X-ray crystallography, cross-linking mass spectrometry, in vitro reconstitution of MCC assembly Nature communications High 36289199

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 480 9182760
2009 Phosphorylation of H2A by Bub1 prevents chromosomal instability through localizing shugoshin. Science (New York, N.Y.) 399 19965387
2012 Phosphoregulation of Spc105 by Mps1 and PP1 regulates Bub1 localization to kinetochores. Current biology : CB 298 22521787
2012 Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. Current biology : CB 241 22521786
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 241 11274370
2004 Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Molecular cell 229 15525512
2005 Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization. Current biology : CB 221 15723797
2009 Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer cell 188 19962666
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 185 11792804
2005 A dual role for Bub1 in the spindle checkpoint and chromosome congression. The EMBO journal 180 15933723
2009 Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Current biology : CB 178 19249208
2010 BUB1 and BUBR1: multifaceted kinases of the cell cycle. Trends in biochemical sciences 175 20888775
1998 The hBUB1 and hBUBR1 kinases sequentially assemble onto kinetochores during prophase with hBUBR1 concentrating at the kinetochore plates in mitosis. Chromosoma 161 9914370
2002 Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer research 160 11782350
2014 Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint. Genes & development 159 24402315
2011 Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. The Journal of cell biology 157 21646403
2003 Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer--association with tumour cell proliferation. The Journal of pathology 146 12692836
1998 Fission yeast bub1 is a mitotic centromere protein essential for the spindle checkpoint and the preservation of correct ploidy through mitosis. The Journal of cell biology 143 9864354
2015 A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint. eLife 123 25611342
2006 Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Molecular biology of the cell 123 16760428
2012 Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction. The Journal of cell biology 114 22331848
2008 Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. Journal of virology 102 18922873
2007 Bub1 kinase targets Sgo1 to ensure efficient chromosome biorientation in budding yeast mitosis. PLoS genetics 97 18081426
2011 Bub1 and BubR1: at the interface between chromosome attachment and the spindle checkpoint. Molecular and cellular biology 96 21628528
2004 Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1. Proceedings of the National Academy of Sciences of the United States of America 96 14732683
2015 Distinct domains in Bub1 localize RZZ and BubR1 to kinetochores to regulate the checkpoint. Nature communications 95 26031201
2001 Fission yeast Bub1 is essential in setting up the meiotic pattern of chromosome segregation. Nature cell biology 93 11331883
2016 The Bub1-Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation. Nature communications 90 26912231
2007 BUB1 mediation of caspase-independent mitotic death determines cell fate. The Journal of cell biology 89 17620410
2018 Distinct Roles of RZZ and Bub1-KNL1 in Mitotic Checkpoint Signaling and Kinetochore Expansion. Current biology : CB 88 30415700
2001 Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. International journal of cancer 86 11400114
1999 Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Japanese journal of cancer research : Gann 84 10543255
2012 Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression. The Journal of cell biology 83 23209306
2008 Structure and substrate recruitment of the human spindle checkpoint kinase Bub1. Molecular cell 83 18995837
2001 Bub1 is activated by the protein kinase p90(Rsk) during Xenopus oocyte maturation. Current biology : CB 82 11231148
2002 The spindle checkpoint kinase bub1 and cyclin e/cdk2 both contribute to the establishment of meiotic metaphase arrest by cytostatic factor. Current biology : CB 80 12123578
1998 Localization of the Drosophila checkpoint control protein Bub3 to the kinetochore requires Bub1 but not Zw10 or Rod. Chromosoma 80 9914369
2015 The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling. Science signaling 78 25564677
2000 Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma. Cancer letters 75 10960763
2000 Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer. Genes, chromosomes & cancer 73 10992296
2020 Untangling the contribution of Haspin and Bub1 to Aurora B function during mitosis. The Journal of cell biology 72 32027339
2013 Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology 72 23747338
2008 Kinetochore-microtubule interactions "in check" by Bub1, Bub3 and BubR1: The dual task of attaching and signalling. Cell cycle (Georgetown, Tex.) 69 18594200
2014 BuGZ is required for Bub3 stability, Bub1 kinetochore function, and chromosome alignment. Developmental cell 68 24462187
2009 Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. Cancer research 67 19117986
2015 Dissecting the roles of human BUB1 in the spindle assembly checkpoint. Journal of cell science 66 26148513
2015 Bub1 is required for maintaining cancer stem cells in breast cancer cell lines. Scientific reports 65 26522589
2006 KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome. The Journal of biological chemistry 62 17158872
2004 Phosphorylation and activation of Bub1 on unattached chromosomes facilitate the spindle checkpoint. The EMBO journal 62 15241477
2006 Bub1 prevents chromosome misalignment and precocious anaphase during mouse oocyte meiosis. Cell cycle (Georgetown, Tex.) 59 16969117
2000 Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer. Japanese journal of cancer research : Gann 58 10835495
1999 Mutation analysis of hBUB1 in aneuploid HNSCC and lung cancer cell lines. Cancer letters 58 10395177
2003 Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts. Cancer research 57 12782591
2021 BUB1 drives the occurrence and development of bladder cancer by mediating the STAT3 signaling pathway. Journal of experimental & clinical cancer research : CR 56 34852826
2019 Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex. The EMBO journal 56 30782962
2018 The BUB3-BUB1 Complex Promotes Telomere DNA Replication. Molecular cell 55 29727616
1999 The mouse mitotic checkpoint gene bub1b, a novel bub1 family member, is expressed in a cell cycle-dependent manner. Genomics 55 9889005
2016 Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524. eLife 54 26885717
2009 Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Proceedings of the National Academy of Sciences of the United States of America 52 19617567
2021 Bub1 kinase in the regulation of mitosis. Animal cells and systems 48 33717411
2002 hBUB1 defects in leukemia and lymphoma cells. Oncogene 48 12096343
2007 Surveillance mechanism linking Bub1 loss to the p53 pathway. Proceedings of the National Academy of Sciences of the United States of America 47 17488820
2001 Expression of Bub1 gene correlates with tumor proliferating activity in human gastric carcinomas. Pathobiology : journal of immunopathology, molecular and cellular biology 46 11641614
2011 The kinetochore protein Bub1 participates in the DNA damage response. DNA repair 45 22071147
2004 Disruption of astral microtubule contact with the cell cortex activates a Bub1, Bub3, and Mad3-dependent checkpoint in fission yeast. Molecular biology of the cell 45 15146064
2017 MiR-490-5p Suppresses Cell Proliferation and Invasion by Targeting BUB1 in Hepatocellular Carcinoma Cells. Pharmacology 44 28810242
2017 Plk1 bound to Bub1 contributes to spindle assembly checkpoint activity during mitosis. Scientific reports 42 28821799
2009 The crystal structure of the N-terminal region of BUB1 provides insight into the mechanism of BUB1 recruitment to kinetochores. Structure (London, England : 1993) 42 19141287
2008 Overexpression of the mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas. Cellular oncology : the official journal of the International Society for Cellular Oncology 42 18791270
1999 Phosphorylation of human MAD1 by the BUB1 kinase in vitro. Biochemical and biophysical research communications 42 10198256
2007 Bub1: escapades in a cellular world. Cell cycle (Georgetown, Tex.) 39 17643075
2016 Bub3-Bub1 Binding to Spc7/KNL1 Toggles the Spindle Checkpoint Switch by Licensing the Interaction of Bub1 with Mad1-Mad2. Current biology : CB 38 27618268
2010 Sgo1 establishes the centromeric cohesion protection mechanism in G2 before subsequent Bub1-dependent recruitment in mitosis. Journal of cell science 37 20124418
2009 Bub1 and Bub3 promote the conversion from monopolar to bipolar chromosome attachment independently of shugoshin. EMBO reports 36 19680287
2014 Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1. Journal of virology 34 24741095
2007 Bub1 is a fission yeast kinetochore scaffold protein, and is sufficient to recruit other spindle checkpoint proteins to ectopic sites on chromosomes. PloS one 34 18094750
1998 Human Bub1: a putative spindle checkpoint kinase closely linked to cell proliferation. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 34 9790499
2001 Mitotic checkpoint genes hBUB1, hBUB1B, hBUB3 and TTK in human bladder cancer, screening for mutations and loss of heterozygosity. Carcinogenesis 33 11323402
2011 Centromere-tethered Mps1 pombe homolog (Mph1) kinase is a sufficient marker for recruitment of the spindle checkpoint protein Bub1, but not Mad1. Proceedings of the National Academy of Sciences of the United States of America 32 22184248
2001 mei-41 and bub1 block mitosis at two distinct steps in response to incomplete DNA replication in Drosophila embryos. Current biology : CB 31 11676920
2021 Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling. Current biology : CB 29 34861183
2017 Meikin-associated polo-like kinase specifies Bub1 distribution in meiosis I. Genes to cells : devoted to molecular & cellular mechanisms 29 28497540
2021 Molecular mechanism of Mad1 kinetochore targeting by phosphorylated Bub1. EMBO reports 28 34013668
2014 Substrate-specific activation of the mitotic kinase Bub1 through intramolecular autophosphorylation and kinetochore targeting. Structure (London, England : 1993) 28 25308863
2018 Malonylation of histone H2A at lysine 119 inhibits Bub1-dependent H2A phosphorylation and chromosomal localization of shugoshin proteins. Scientific reports 27 29769606
2009 TAp73alpha binds the kinetochore proteins Bub1 and Bub3 resulting in polyploidy. Cell cycle (Georgetown, Tex.) 27 19182530
2021 Inhibition of BUB1 suppresses tumorigenesis of osteosarcoma via blocking of PI3K/Akt and ERK pathways. Journal of cellular and molecular medicine 26 34337852
2015 Bub1 autophosphorylation feeds back to regulate kinetochore docking and promote localized substrate phosphorylation. Nature communications 26 26399325
2000 Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer. Cancer research 26 10969775
2022 The spindle checkpoint proteins BUB1 and BUBR1: (SLiM)ming down to the basics. Trends in biochemical sciences 25 35184951
2020 Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma. Cancers 25 32781708
2018 BUB-1 promotes amphitelic chromosome biorientation via multiple activities at the kinetochore. eLife 25 30547880
2011 Aurora B hyperactivation by Bub1 overexpression promotes chromosome missegregation. Cell cycle (Georgetown, Tex.) 25 22033440
2014 BUB1 mRNA is significantly co-expressed with AURKA and AURKB mRNA in advanced-stage ovarian serous carcinoma. Virchows Archiv : an international journal of pathology 24 24756216
2010 BUB3 that dissociates from BUB1 activates caspase-independent mitotic death (CIMD). Cell death and differentiation 24 20057499
2001 Mutation analysis of hBUB1, hBUBR1 and hBUB3 genes in glioblastomas. Acta neuropathologica 24 11355300
2022 Juxtaposition of Bub1 and Cdc20 on phosphorylated Mad1 during catalytic mitotic checkpoint complex assembly. Nature communications 23 36289199
2015 Spindle Checkpoint Factors Bub1 and Bub2 Promote DNA Double-Strand Break Repair by Nonhomologous End Joining. Molecular and cellular biology 23 25963654
2008 Overexpression of the mitotic spindle assembly checkpoint genes hBUB1, hBUBR1 and hMAD2 in thyroid carcinomas with aggressive nature. Anticancer research 22 18383837
2019 RETRACTED: Serine/threonine kinase BUB1 promotes proliferation and radio-resistance in glioblastoma. Pathology, research and practice 21 31272759