Affinage

MIS18A

Protein Mis18-alpha · UniProt Q9NYP9

Round 2 corrected
Length
233 aa
Mass
25.9 kDa
Annotated
2026-04-28
39 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MIS18A is a core subunit of the Mis18 complex that primes centromeric chromatin for de novo CENP-A deposition during telophase and G1 phase. MIS18A heteroligomerizes with MIS18β through C-terminal coiled-coil and Yippee domains, forming a 4:2 hexameric scaffold that binds two copies of M18BP1 via its N-terminal region; this assembly is required for centromere recognition and subsequent recruitment of the CENP-A loading factor HJURP (PMID:17199038, PMID:26942680, PMID:28059702). Cell-cycle gating of Mis18 complex formation is enforced by CDK1-mediated phosphorylation of M18BP1, which blocks its association with the MIS18A–MIS18β scaffold outside of G1, while Plk1 activity promotes centromeric localization of the complex (PMID:25036634, PMID:28059702). HJURP binding to the MIS18A–MIS18β coiled-coil domains disrupts the heterotetramer and displaces MIS18A from centromeres, thereby limiting CENP-A deposition to a single event per cell cycle (PMID:26942680).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2007 High

    The discovery that MIS18A, MIS18β, and M18BP1 form a telophase-G1-specific centromere complex essential for de novo CENP-A loading established the first upstream licensing step for centromere maintenance, answering how cells prepare centromeric chromatin for histone variant deposition.

    Evidence RNAi knockdown of each subunit in human cells combined with live-cell imaging, co-IP, and pharmacological rescue with HDAC inhibitor trichostatin A

    PMID:17199038

    Open questions at the time
    • Physical stoichiometry and architecture of the Mis18 complex were undefined
    • Direct enzymatic activity (e.g., acetyltransferase vs. recruitment of acetylases) was not resolved
    • How the complex is restricted to specific cell-cycle windows was unknown
  2. 2014 High

    Identification of Plk1 as a positive regulator and CDK activity as a negative regulator of Mis18 complex centromere recruitment answered how CENP-A deposition is coupled to cell-cycle progression, revealing a two-step kinase gating mechanism.

    Evidence Chemical-genetic Plk1 inhibition, CDK inhibitor treatment, RNAi, and CENP-A incorporation assays in human cells

    PMID:25036634

    Open questions at the time
    • Direct phosphorylation sites on Mis18 subunits or M18BP1 were not mapped
    • How Plk1 mechanistically promotes centromere targeting of MIS18A was unclear
  3. 2016 High

    Biochemical reconstitution of the MIS18A–MIS18β heterotetramer and demonstration that HJURP binding disrupts it resolved the architectural basis of centromere priming and provided a self-limiting mechanism that restricts CENP-A loading to one event per cycle.

    Evidence In vitro pulldown, size-exclusion chromatography, coiled-coil domain mutagenesis, and immunofluorescence in human cells

    PMID:26942680

    Open questions at the time
    • Atomic-resolution structure of the MIS18A–MIS18β heterotetramer was not available
    • Whether heterotetramer disruption is sufficient for centromere eviction in vivo was not directly tested
  4. 2016 Medium

    Linking the acetyltransferase KAT7 to the Mis18 complex via M18BP1 clarified the chromatin-modifying effector arm through which the complex primes centromeres for histone exchange, resolving a question raised by earlier HDAC inhibitor rescue experiments.

    Evidence Co-IP of KAT7 with M18BP1, CRISPR knockout, ChIP, and ectopic chromatin tethering assay

    PMID:27270040

    Open questions at the time
    • MIS18A was not directly shown to contact KAT7; interaction is via M18BP1
    • Whether KAT7 is the sole acetyltransferase recruited by the Mis18 complex was not addressed
  5. 2017 High

    Reconstitution of a 4:2 MIS18A:MIS18β hexamer bound to two M18BP1 copies, and mapping of CDK1 phosphorylation sites on M18BP1 that block this interaction, provided a precise structural and regulatory model for cell-cycle-restricted Mis18 complex assembly.

    Evidence SEC-MALS, cross-linking mass spectrometry, recombinant reconstitution, phospho-mutagenesis, and immunofluorescence

    PMID:28059702

    Open questions at the time
    • High-resolution structure (cryo-EM or crystal) of the full hexameric complex was not obtained
    • How Plk1 counteracts CDK1-mediated inhibition at the structural level remains unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include the atomic-resolution structure of the complete Mis18 complex, the mechanism by which Plk1 promotes centromere targeting, and whether MIS18A plays roles beyond centromere priming (e.g., in response to proliferative signaling).
  • No high-resolution structure of the full Mis18 hexamer or its centromere-bound state exists
  • The direct Plk1 substrate(s) within the Mis18 complex are not identified
  • Regulation of MIS18A expression by mitogenic signaling (e.g., FAM72A/EGF axis) is supported only by preliminary evidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005694 chromosome 4
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-4839726 Chromatin organization 2
Partners
HJURPKAT7MIS18BP1OIP5PLK1
Complex memberships
Mis18 complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 hMis18α (MIS18A), hMis18β, and M18BP1 form a complex that accumulates specifically at the telophase-G1 centromere and is essential for the subsequent recruitment of de novo-synthesized CENP-A. RNAi knockdown of any of the three subunits abolishes centromeric CENP-A recruitment, leading to misaligned chromosomes, anaphase missegregation, and interphase micronuclei. The histone deacetylase inhibitor trichostatin A suppresses loss of CENP-A recruitment in hMis18α RNAi cells, implicating acetylation status of centromere chromatin in the priming mechanism. RNAi knockdown, live-cell imaging, immunofluorescence, co-immunoprecipitation, cell-cycle staging Developmental cell High 17199038
2014 Polo-like kinase 1 (Plk1) localizes to centromeres and is required to initiate CENP-A deposition by promoting the centromeric localization of the Mis18 complex, including MIS18A. CDK activity independently inhibits Mis18 complex assembly. Bypassing both regulatory steps uncouples CENP-A deposition from cell-cycle progression and causes mitotic defects, establishing a two-step Plk1/CDK regulatory paradigm for CENP-A deposition. Chemical-genetic Plk1 inhibition, CDK inhibitor treatment, RNAi, immunofluorescence, co-immunoprecipitation, CENP-A incorporation assay Cell High 25036634
2016 MIS18A and MIS18β form a heterotetramer through their C-terminal coiled-coil domains; this heterotetramer is required for M18BP1 binding and centromere recognition. HJURP is recruited to centromeres through a direct interaction between its centromere targeting domain and the MIS18A-MIS18β C-terminal coiled-coil domains. HJURP binding disrupts the MIS18A-MIS18β heterotetramer and removes MIS18A from centromeres, restricting CENP-A deposition to a single event per cell cycle. Co-immunoprecipitation, in vitro pulldown, size-exclusion chromatography, domain mapping, mutagenesis, immunofluorescence Molecular cell High 26942680
2016 The acetyltransferase KAT7/HBO1/MYST2 interacts with the CENP-A assembly factor M18BP1 (a component of the Mis18 complex containing MIS18A). KAT7 knockout reduces centromeric CENP-A assembly and increases chromosome misalignment; tethering KAT7 to an ectopic alphoid DNA site removes H3K9me3 and stimulates CENP-A assembly, indicating that KAT7-containing acetyltransferases associated with the Mis18 complex provide competence for histone exchange on centromeric DNA. Co-immunoprecipitation, CRISPR knockout, immunofluorescence, chromatin tethering assay, ChIP Developmental cell Medium 27270040
2017 A human MIS18A:MIS18β complex forms a 4:2 hexamer (via Yippee domains) that binds two copies of M18BP1 through M18BP1's 140 N-terminal residues. CDK1 phosphorylation at two conserved sites in this M18BP1 N-terminal region destabilizes binding to the MIS18A:MIS18β scaffold, restricting Mis18 complex assembly and centromere recruitment to G1 phase. Structural biochemistry (SEC-MALS, cross-linking MS), recombinant protein reconstitution, phospho-mutagenesis, viral 2A co-expression system, immunofluorescence eLife High 28059702
2025 FAM72A, expressed from the divergent |Srgap2-Fam72a| master gene locus upon EGF stimulation, downregulates MIS18A (a tightly cell cycle-regulated gene) and interferes with AKT1 signaling by reducing phospho-AKT1 (Ser473), thereby favoring the MAPK1 route to promote cellular proliferation. Reporter assays (IGR promoter activity), siRNA knockdown, Western blotting, RT-qPCR, EGF stimulation paradigm Cell cycle (Georgetown, Tex.) Low 41414706

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2000 The DNA sequence of human chromosome 21. Nature 808 10830953
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
2000 Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. The Biochemical journal 480 11001876
2005 Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 466 15897552
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
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2007 Priming of centromere for CENP-A recruitment by human hMis18alpha, hMis18beta, and M18BP1. Developmental cell 338 17199038
2013 High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 297 24270810
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2014 Polo-like kinase 1 licenses CENP-A deposition at centromeres. Cell 152 25036634
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
1998 Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues. Biochemistry 102 9708987
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2016 Licensing of Centromeric Chromatin Assembly through the Mis18α-Mis18β Heterotetramer. Molecular cell 84 26942680
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2016 KAT7/HBO1/MYST2 Regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation. Developmental cell 79 27270040
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2017 CDK-regulated dimerization of M18BP1 on a Mis18 hexamer is necessary for CENP-A loading. eLife 72 28059702
2022 MYC multimers shield stalled replication forks from RNA polymerase. Nature 63 36424410
2007 Effectiveness of cell-adsorbed bacteriocin produced by Lactobacillus curvatus CWBI-B28 and selected essential oils to control Listeria monocytogenes in pork meat during cold storage. Letters in applied microbiology 18 17309503
2006 Bacteriocin activity by Lactobacillus curvatus CWBI-B28 to inactivate Listeria monocytogenes in cold-smoked salmon during 4 degrees C storage. Journal of food protection 18 16715806
2021 Functional Genomic Insights into Probiotic Bacillus siamensis Strain B28 from Traditional Korean Fermented Kimchi. Foods (Basel, Switzerland) 15 34441683
1993 Preparation of N epsilon B28-monoazidobenzoyl insulin-like growth factor I and photoaffinity labeling of insulin-like growth factor I receptor. Peptides 4 8483809
2019 LncRNAs down-regulate Myh1, Casr, and Mis18a expression in the Substantia Nigra of aged male rats. Aging 2 31576812
2024 MIS18A upregulation promotes cell viability, migration and tumor immune evasion in lung adenocarcinoma. Oncology letters 1 38910901
2025 Cell cycle-regulated expression of Fam72a from the |Srgap2-Fam72a| master gene leads to Mis18a downregulation. Cell cycle (Georgetown, Tex.) 0 41414706