Affinage

MIS18BP1

Mis18-binding protein 1 · UniProt Q6P0N0

Round 2 corrected
Length
1132 aa
Mass
129.1 kDa
Annotated
2026-04-28
50 papers in source corpus 18 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MIS18BP1 is a central regulator of centromere identity that couples cell-cycle signaling to CENP-A nucleosome assembly and, independently, activates condensin II for mitotic chromosome condensation. It functions as a core subunit of the trimeric Mis18 complex (with Mis18α and Mis18β), where CDK1 phosphorylation of its N-terminal region restricts complex formation and centromere recruitment to G1 phase; upon dephosphorylation, M18BP1 dimerizes on a Mis18α:Mis18β hexameric scaffold and engages centromeric chromatin through multivalent contacts including direct binding to CENP-A nucleosomes (via a CENP-C-like motif in non-mammalian vertebrates), interaction with CENP-C through its SANTA domain, and recognition of the CCAN, thereby recruiting the CENP-A chaperone HJURP for new CENP-A deposition (PMID:17199038, PMID:28059702, PMID:28743005, PMID:41629527). During metaphase, M18BP1 competitively inhibits HJURP access to centromeres via CENP-C binding, constituting one of two mechanisms that restrict CENP-A loading to the appropriate cell-cycle window (PMID:37141119). At mitotic entry, M18BP1 directly binds the condensin II subunit CAP-G2, displacing the antagonist MCPH1 and activating condensin II to promote chromosome condensation, revealing a dual role in centromere maintenance and higher-order chromosome organization (PMID:40614722).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    Identification of M18BP1 as a component of a three-subunit Mis18 complex that localizes to centromeres in telophase–G1 and is essential for new CENP-A loading established the gene's foundational role in centromere propagation.

    Evidence RNAi knockdown in C. elegans and human cells with live-cell imaging and immunofluorescence, replicated across two independent labs

    PMID:17199038 PMID:17339379

    Open questions at the time
    • Mechanism by which M18BP1 is recruited to centromeres was unknown
    • How M18BP1 promotes CENP-A loading was not determined
    • Cell-cycle restriction mechanism was unresolved
  2. 2011 High

    Discovery that CENP-C directly recruits M18BP1 to centromeres provided the first molecular link between existing CENP-A chromatin and the CENP-A assembly machinery, with the SANT/SANTA domain mediating this interaction.

    Evidence Co-IP, pulldown, RNAi depletion, immunofluorescence, and domain mapping in human cells and mouse ES cells

    PMID:21911481 PMID:22540025

    Open questions at the time
    • Whether M18BP1 directly recognizes CENP-A nucleosomes in addition to CENP-C was unknown
    • Structural basis of the SANTA domain–CENP-C interaction was not resolved
  3. 2016 High

    Reconstitution of the Mis18α:Mis18β heterotetramer and demonstration that this scaffold is required for M18BP1 binding and HJURP recruitment defined the biochemical architecture through which M18BP1 operates, while the discovery that KAT7 interacts with M18BP1 linked the complex to chromatin acetylation.

    Evidence Biochemical reconstitution, domain mutagenesis, co-IP, and KAT7 knockout in HeLa cells

    PMID:26942680 PMID:27270040

    Open questions at the time
    • Stoichiometry and geometry of M18BP1 on the Mis18 scaffold were not yet resolved
    • How KAT7 acetylation facilitates CENP-A deposition mechanistically was unclear
  4. 2017 High

    Determination that CDK1 phosphorylation of two conserved N-terminal sites on M18BP1 blocks its binding to the Mis18α:Mis18β 4:2 hexamer, restricting Mis18 complex assembly and centromere recruitment to G1, resolved the long-standing question of how CENP-A loading is cell-cycle-gated; separately, M18BP1 was shown to directly bind CENP-A nucleosomes in Xenopus through a CENP-C-like motif.

    Evidence Biochemical reconstitution with SEC and mass spectrometry in human cells; nucleosome pulldowns and competition binding assays in Xenopus egg extracts

    PMID:28059702 PMID:28743005

    Open questions at the time
    • Mammalian M18BP1 lacks the CENP-C-like motif, leaving the mammalian CENP-A nucleosome recognition mechanism unresolved
    • Phosphorylation of M18BP1's CENP-A-nucleosome-binding region was not yet characterized
  5. 2019 High

    Demonstration that CDK phosphorylation of Xenopus M18BP1 is required for its SANTA-domain-mediated CENP-C binding in metaphase, and that this metaphase priming is necessary for subsequent interphase CENP-A assembly, revealed a two-step phospho-regulatory model linking metaphase centromere licensing to G1 CENP-A deposition.

    Evidence Phosphomutant analysis, co-IP, and functional rescue in Xenopus egg extracts

    PMID:30606714

    Open questions at the time
    • Exact phospho-sites governing the CENP-A nucleosome binding switch were not yet mapped
    • Whether an analogous priming step exists in mammalian cells was unclear
  6. 2021 Medium

    In C. elegans, which lacks HJURP, direct binding of KNL-2 (M18BP1 ortholog) to the CENP-A N-terminal tail partially substitutes for a dedicated CENP-A chaperone, broadening the functional repertoire of M18BP1 across evolution.

    Evidence In vitro binding assays, RNAi, and CENP-A N-tail deletion mutants in C. elegans and C. briggsae

    PMID:33852350

    Open questions at the time
    • Whether this chaperone-like activity exists in vertebrate M18BP1 is unknown
    • Structural basis of KNL-2–CENP-A tail interaction not determined
  7. 2023 High

    Reconstitution of competitive binding showed that M18BP1 occupies CENP-C at metaphase centromeres to block HJURP access, establishing M18BP1 as an active inhibitor of premature CENP-A loading rather than merely a passive licensing factor.

    Evidence Competitive binding assays, immunodepletion, and phosphomutant analysis in Xenopus egg extracts

    PMID:37141119

    Open questions at the time
    • Quantitative parameters of the competition (affinities, stoichiometry) not measured
    • Whether this inhibitory role is conserved in mammals was not tested
  8. 2024 Medium

    Discovery that KNL-2 promotes outer kinetochore assembly in C. elegans meiosis I independently of CENP-A loading, by recruiting MEL-28/ELYS through its N-terminal domain, revealed a non-canonical function of the M18BP1 family beyond centromere maintenance; additionally, tethering experiments in chicken DT40 cells showed that M18BP1 can recruit CENP-A to ectopic sites independently of CENP-C.

    Evidence RNAi and auxin-inducible degron depletions with domain mutants in C. elegans; artificial tethering and conditional knockouts in DT40 cells

    PMID:38319136 PMID:39353426

    Open questions at the time
    • Whether the meiotic kinetochore assembly role exists in vertebrates is unknown
    • Mechanism by which tethered M18BP1 loads CENP-A without CENP-C is not defined
  9. 2025 High

    Identification of M18BP1 as the direct binding partner and activator of condensin II (via CAP-G2), which displaces the interphase antagonist MCPH1 at mitotic entry, revealed a second major function of M18BP1 in chromosome condensation independent of its CENP-A loading role.

    Evidence Co-IP, competitive binding assays, loss-of-function studies, and proteomic approaches in human cells

    PMID:40614722

    Open questions at the time
    • How cell-cycle signals trigger the MCPH1-to-M18BP1 switch on CAP-G2 is not resolved
    • Whether condensin II activation and CENP-A loading are coordinated through shared M18BP1 pools is unknown
  10. 2026 High

    First structural determination of the SANTA domain and identification of at least four centromere-localization determinants in M18BP1 — including SANTA, linear CCAN-binding motifs, and dimerization-dependent multivalent recognition of old CENP-A — provided an integrated structural framework for how M18BP1 bridges the Mis18 scaffold to centromeric chromatin; phospho-regulation of M18BP1–CENP-A nucleosome binding was also resolved in Xenopus.

    Evidence Cryo-EM/structural analysis, artificial dimerization, mutagenesis in human cells; phosphomutant nucleosome binding assays in Xenopus egg extracts

    PMID:41629527 PMID:41680291

    Open questions at the time
    • Full atomic-resolution structure of M18BP1 in complex with the Mis18 hexamer is lacking
    • How PLK1 recruitment by dimerized M18BP1 triggers HJURP loading is not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include how mammalian M18BP1 recognizes CENP-A nucleosomes in the absence of the CENP-C-like motif found in non-mammalian vertebrates, how M18BP1's dual roles in CENP-A loading and condensin II activation are temporally and spatially coordinated within a single cell cycle, and whether the meiotic kinetochore assembly function of the M18BP1 family is conserved beyond nematodes.
  • Mammalian CENP-A nucleosome recognition mechanism for M18BP1 is unresolved
  • Coordination between CENP-A loading and condensin II activation by shared M18BP1 is unexplored
  • Conservation of meiotic kinetochore assembly function outside C. elegans is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0042393 histone binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005694 chromosome 7 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-4839726 Chromatin organization 5
Partners
CAPG2CENPCELYSHJURPKAT7MCPH1MIS18AMIS18B
Complex memberships
Condensin II (via CAP-G2 binding)Mis18 complex (Mis18α:Mis18β:MIS18BP1)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 M18BP1 (initially called KNL-2 in C. elegans, with human homologue identified) is part of a three-protein Mis18 complex (hMis18α, hMis18β, M18BP1) that accumulates specifically at telophase-G1 centromeres and is essential for the subsequent recruitment of newly synthesized CENP-A; RNAi knockdown of any subunit abolishes new CENP-A loading and causes chromosome missegregation defects. RNAi knockdown, live-cell imaging, immunofluorescence, functional genomics screen in C. elegans Developmental cell / The Journal of cell biology High 17199038 17339379
2011 CENP-C recruits M18BP1 to centromeres during metaphase through a direct physical interaction; depletion of CENP-C prevents M18BP1 targeting and inhibits CENP-A chromatin assembly. M18BP1 directly binds conserved domains within CENP-C, providing a molecular link between existing CENP-A chromatin and the CENP-A assembly machinery. RNAi depletion, Co-IP, pulldown assays, immunofluorescence, functional rescue experiments The Journal of cell biology High 21911481 22540025
2012 M18BP1 displays cell cycle-regulated association with centromeric chromatin in mouse ES cells, enriched from late anaphase through G1. The interaction domain for CENP-C maps to a central region of M18BP1 containing a conserved SANT domain, and to the C-terminus of CENP-C. Interaction screen against 16 core centromeric proteins, domain mapping, Co-IP, immunofluorescence, knockdown Nucleus Medium 22540025
2016 Mis18α and Mis18β form a heterotetramer through their C-terminal coiled-coil domains, and this heterotetramer formation is required for M18BP1 (Mis18BP1) binding and centromere recognition. HJURP recruitment to centromeres occurs through direct interaction with the Mis18α-β coiled-coil domains and disrupts the Mis18 complex. Biochemical reconstitution, co-immunoprecipitation, domain mutagenesis, immunofluorescence Molecular cell High 26942680
2016 M18BP1 interacts with the acetyltransferase KAT7/HBO1/MYST2, and this interaction is required for CENP-A assembly; KAT7 knockout reduces centromeric CENP-A assembly and causes chromosome misalignment and micronuclei formation, linking the Mis18 complex to chromatin acetylation as a prerequisite for CENP-A deposition. Co-IP, KO in HeLa cells, immunofluorescence, artificial tethering, ChIP Developmental cell Medium 27270040
2017 In human cells, a Mis18α:Mis18β 4:2 hexamer (arranged through specific Yippee domain contacts) binds two copies of M18BP1 through M18BP1's 140 N-terminal residues. CDK1 phosphorylates two conserved sites in this N-terminal region, destabilizing binding to the hexamer and restricting Mis18 complex formation and centromere recruitment to G1 phase. M18BP1 dimerization via the Mis18 scaffold is required for CENP-A loading. Biochemical reconstitution, SEC, mutagenesis, mass spectrometry, cell biology with 2A peptide co-expression strategy, immunofluorescence eLife High 28059702
2017 In Xenopus, M18BP1 directly and cell-cycle-dependently binds CENP-A nucleosomes through a motif conserved in non-mammalian vertebrates that resembles the CENP-C CENP-A nucleosome binding motif; CENP-C competes with M18BP1 for binding to CENP-A nucleosomes at centromeres. Both CENP-C and M18BP1 recruit HJURP for new CENP-A assembly. Xenopus egg extract cell-free system, nucleosome pulldown, competition binding assays, domain mutagenesis, immunodepletion, immunofluorescence Developmental cell High 28743005
2015 The CENP-C motif sequence is present in M18BP1 proteins of fish and some other non-mammalian vertebrates but not in mammals, suggesting an evolutionary variation in the mechanism by which M18BP1 recognizes centromeric nucleosomes across vertebrate taxa. Comparative sequence analysis, BLASTP, evolutionary bioinformatics F1000Research Low 27127616
2019 In Xenopus, Cdk phosphorylation of M18BP1 is necessary for M18BP1 to bind CENP-C via its SANTA domain and localize to centromeres in metaphase; disrupting this metaphase M18BP1/CENP-C interaction also causes defective nuclear localization of M18BP1 in interphase, resulting in failure of CENP-A nucleosome assembly. Xenopus egg extract, phosphomutant analysis, co-immunoprecipitation, immunofluorescence, functional rescue The EMBO journal High 30606714
2021 In C. elegans, the N-terminal tail of CENP-A (which contains an extended predicted structured region essential for CENP-A chromatin assembly) directly binds KNL-2 (the C. elegans ortholog of M18BP1); this interaction partially substitutes for the function of HJURP/Scm3 in organisms lacking a dedicated CENP-A chaperone. In vitro binding assays, RNAi depletion, CENP-A N-tail deletion mutants, immunofluorescence in C. elegans and C. briggsae Molecular biology of the cell Medium 33852350
2023 M18BP1 (specifically the M18BP1.S subunit in Xenopus) binds to CENP-C in metaphase to competitively inhibit HJURP's access to centromeres, representing one of two mechanisms that restrict CENP-A assembly to G1; the other mechanism is CDK-dependent phosphorylation of HJURP that blocks its interaction with CENP-C. Xenopus egg extract cell-free system, phosphomutant analysis, competitive binding assays, immunodepletion The Journal of cell biology High 37141119
2024 In C. elegans oocytes during meiosis I, KNL-2 (M18BP1 ortholog) promotes outer kinetochore assembly through a non-canonical pathway independent of its CENP-A loading activity; KNL-2 recruits the nucleoporin MEL-28/ELYS to meiotic kinetochores through a specific N-terminal domain, and co-depletion of CENP-A/CENP-C with KNL-2 fully prevents outer kinetochore assembly. RNAi and auxin-inducible degron depletion, engineered domain mutants, immunofluorescence, C. elegans genetics Current biology Medium 39353426
2024 In chicken DT40 cells, Knl2 (MIS18BP1) tethering can recruit CENP-A to non-centromeric loci independently of CENP-C, and tethering of CENP-C or CENP-I can induce CENP-A incorporation even in the absence of Knl2, showing that multiple independent pathways exist for CENP-A recruitment to artificial kinetochore sites. Artificial tethering assay, auxin-inducible degron knockout, Co-IP, immunofluorescence in DT40 cells Journal of cell science Medium 38319136
2025 M18BP1 directly binds the CAP-G2 subunit of condensin II; during interphase, the condensin II antagonist MCPH1 also binds CAP-G2 and outcompetes M18BP1; at mitotic onset, a switch from MCPH1 to M18BP1 binding activates condensin II and promotes chromosome condensation. This identifies M18BP1 as the elusive activator of condensin II at mitotic entry. Genetic and proteomic approaches, Co-IP, competitive binding assays, loss-of-function studies, cell biology Molecular cell High 40614722
2026 In human cells, artificial M18BP1 dimerization bypasses the need for MIS18α/β, enabling identification of at least four determinants of M18BP1 centromere localization including the SANTA domain (first structure reported) and linear motifs in disordered regions that interact with the 16-subunit CCAN. Cell-cycle-dependent dimerization of M18BP1 on MIS18α/β promotes multivalent recognition of old CENP-A and associated proteins, followed by PLK1 and HJURP recruitment for new CENP-A deposition. Artificial dimerization strategy, cryo-EM/structural determination of SANTA domain, mutagenesis, Co-IP, immunofluorescence, cell biology in human cells The EMBO journal High 41629527
2026 In Xenopus, cell-cycle-dependent phosphorylation of M18BP1 disrupts its binding to CENP-A nucleosomes in metaphase; when this phosphorylation is relieved in interphase, M18BP1 binds CENP-A nucleosomes to promote new CENP-A nucleosome assembly. This phospho-regulatory switch provides a mechanism for restricting CENP-A assembly to interphase. Xenopus egg extract, phosphomutant analysis, nucleosome binding assays, immunofluorescence EMBO reports High 41680291
2025 Phosphorylation of Xenopus M18BP1 by CDK disrupts its binding to CENP-A nucleosomes in metaphase, and relief of this phosphorylation in interphase enables M18BP1 binding to CENP-A nucleosomes to drive new CENP-A assembly (preprint version of the EMBO reports 2026 study). Xenopus egg extract, phosphomutant analysis, nucleosome binding assays bioRxivpreprint High 40791504

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2007 Priming of centromere for CENP-A recruitment by human hMis18alpha, hMis18beta, and M18BP1. Developmental cell 338 17199038
2006 Phosphoproteome analysis of the human mitotic spindle. Proceedings of the National Academy of Sciences of the United States of America 281 16565220
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2007 Functional genomics identifies a Myb domain-containing protein family required for assembly of CENP-A chromatin. The Journal of cell biology 194 17339379
2011 CENP-C recruits M18BP1 to centromeres to promote CENP-A chromatin assembly. The Journal of cell biology 187 21911481
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2018 MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis. Molecular cell 152 30415952
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2017 The human cytoplasmic dynein interactome reveals novel activators of motility. eLife 118 28718761
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2012 CENP-C facilitates the recruitment of M18BP1 to centromeric chromatin. Nucleus (Austin, Tex.) 111 22540025
2018 Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. Cancer cell 101 29478914
2018 Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function. EMBO reports 92 29467282
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2016 Licensing of Centromeric Chromatin Assembly through the Mis18α-Mis18β Heterotetramer. Molecular cell 84 26942680
2016 KAT7/HBO1/MYST2 Regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation. Developmental cell 79 27270040
2017 CDK-regulated dimerization of M18BP1 on a Mis18 hexamer is necessary for CENP-A loading. eLife 72 28059702
2017 Xenopus laevis M18BP1 Directly Binds Existing CENP-A Nucleosomes to Promote Centromeric Chromatin Assembly. Developmental cell 60 28743005
2017 Targeting of Arabidopsis KNL2 to Centromeres Depends on the Conserved CENPC-k Motif in Its C Terminus. The Plant cell 47 28062749
2019 CDK phosphorylation of Xenopus laevis M18BP1 promotes its metaphase centromere localization. The EMBO journal 25 30606714
2015 Possible identification of CENP-C in fish and the presence of the CENP-C motif in M18BP1 of vertebrates. F1000Research 24 27127616
2023 Repression of CENP-A assembly in metaphase requires HJURP phosphorylation and inhibition by M18BP1. The Journal of cell biology 15 37141119
2022 Recurrent Plant-Specific Duplications of KNL2 and Its Conserved Function as a Kinetochore Assembly Factor. Molecular biology and evolution 13 35671323
2021 The N-terminal tail of C. elegans CENP-A interacts with KNL-2 and is essential for centromeric chromatin assembly. Molecular biology of the cell 11 33852350
2025 Condensin II activation by M18BP1. Molecular cell 9 40614722
2024 Artificial tethering of constitutive centromere-associated network proteins induces CENP-A deposition without Knl2 in DT40 cells. Journal of cell science 6 38319136
2019 Depletion of KNL2 Results in Altered Expression of Genes Involved in Regulation of the Cell Cycle, Transcription, and Development in Arabidopsis. International journal of molecular sciences 5 31731608
2021 Mitotic chromosome condensation requires phosphorylation of the centromeric protein KNL-2 in C. elegans. Journal of cell science 4 34734636
2025 MIS18BP1 promotes bladder cancer cell proliferation and growth via inactivating P53 signaling pathway. Medical oncology (Northwood, London, England) 3 40205244
2025 Ubiquitin-dependent proteolysis of KNL2 driven by APC/CCDC20 is critical for centromere integrity and mitotic fidelity. The Plant cell 2 40561118
2026 M18BP1 valency and a distributed interaction footprint determine epigenetic centromere specification in humans. The EMBO journal 1 41629527
2025 Regulation of X. laevis M18BP1 centromeric localization and CENP-A assembly. bioRxiv : the preprint server for biology 1 40791504
2024 Regulation of outer kinetochore assembly during meiosis I and II by CENP-A and KNL-2/M18BP1 in C. elegans oocytes. Current biology : CB 1 39353426
2026 Phosphorylation of Xenopus M18BP1 governs centromeric localization and CENP-A nucleosome assembly. EMBO reports 0 41680291