{"gene":"MKI67","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2016,"finding":"Ki-67 functions as a biological surfactant on the mitotic chromosome periphery, preventing chromosome aggregation after nuclear envelope disassembly. The chromosome separation function correlates with the size and net charge of the protein rather than a specific domain, suggesting a steric and electrostatic charge barrier mechanism. Fluorescence correlation spectroscopy demonstrated high surface density of Ki-67, and dual-colour labelling of both protein termini revealed an extended molecular conformation consistent with brush-like polymer surfactant arrangements.","method":"Truncation mutagenesis, fluorescence correlation spectroscopy, dual-colour live-cell imaging, siRNA depletion with mitotic phenotype readout","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, FCS, live imaging) in a single rigorous study establishing the biophysical mechanism","pmids":["27362226"],"is_preprint":false},{"year":2014,"finding":"Ki-67 is a cell-cycle-regulated protein phosphatase 1 (PP1)-binding protein required for assembly of the perichromosomal compartment. siRNA depletion of Ki-67 causes failure of multiple nucleolar/periphery proteins (NIFK, B23/nucleophosmin, nucleolin, and four novel periphery proteins) to associate with the chromosome periphery, with CLEM showing near-complete loss of the perichromosomal layer. Ki-67 is also involved in phospho-regulation of B23/nucleophosmin.","method":"siRNA depletion, correlative light and electron microscopy (CLEM), co-immunoprecipitation, immunofluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying PP1 as binding partner, CLEM for ultrastructural validation, replicated by multiple downstream studies","pmids":["24867636"],"is_preprint":false},{"year":2016,"finding":"Ki-67 and RepoMan recruit protein phosphatase 1 (PP1) to form mitotic exit phosphatases via an identical, novel mechanism, interacting with a PP1 pocket not engaged by any other known PP1 regulator. Ki-67 distinguishes between distinct PP1 isoforms, and the assembly of the Ki-67:PP1 holoenzyme is dynamically regulated by Aurora B kinase during mitosis.","method":"Structural analysis (NMR/crystallography), biochemical binding assays, mutagenesis, kinase assays with Aurora B","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural and biochemical reconstitution with mutagenesis in a single detailed study","pmids":["27572260"],"is_preprint":false},{"year":2020,"finding":"During mitotic exit, Ki-67 molecular brushes collapse and promote chromosome clustering, which physically displaces large cytoplasmic components (including mature ribosomes) before nuclear envelope assembly, thereby re-establishing nuclear-cytoplasmic compartmentalization. This chromosome clustering function is microtubule-independent.","method":"Live-cell imaging, Ki-67 depletion/rescue, ribosome exclusion assays, HeLa cell manipulations","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistically dissected in two orthogonal readouts (chromosome clustering and ribosome exclusion) with genetic rescue, published in high-tier journal","pmids":["32879492"],"is_preprint":false},{"year":2018,"finding":"Ki-67 and condensins support the structural integrity of mitotic chromosomes through independent yet cooperative mechanisms: Ki-67 localizes to the chromosome periphery while condensins occupy the central axis, and their localization/dynamics are mutually independent. Combined depletion of Ki-67 and SMC2 (condensin core subunit) produces a severe phenotype (ball-like chromosome clusters with no thread-like structures) distinct from either single depletion.","method":"Auxin-inducible degron conditional degradation, immunofluorescence, live-cell imaging in HCT116 cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — auxin-inducible degron for acute protein depletion with clear epistasis readout, two orthogonal depletion combinations","pmids":["29487178"],"is_preprint":false},{"year":2006,"finding":"Ki-67 physically associates with chromatin at the promoter and transcribed regions of the ribosomal RNA (rRNA) gene cluster, and a fraction of Ki-67 co-localizes with the rRNA transcription machinery during interphase and mitosis in proliferating cells; Ki-67 can also be detected at rRNA synthesis sites in quiescent cells, suggesting a role in early steps of rRNA synthesis.","method":"Chromatin immunoprecipitation (ChIP), immunofluorescence co-localization, novel antibody (TuBB-9)","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP provides direct genomic association evidence; single lab, two orthogonal methods","pmids":["16206250"],"is_preprint":false},{"year":2022,"finding":"By pA-DamID genome-wide mapping, Ki-67 associates with large late-replicating genomic domains during early interphase on all chromosomes but shifts toward small chromosomes later in interphase as it is confined to nucleoli. Ki-67 does not detectably control chromatin-chromatin interactions during interphase but competes with the nuclear lamina for interaction with late-replicating DNA and controls replication timing of (peri)centromeric regions.","method":"pA-DamID genomic mapping, nucleolar perturbation experiments, replication timing assays in human cell lines","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide mapping with functional perturbation, single lab","pmids":["36245428"],"is_preprint":false},{"year":2024,"finding":"Ki-67 plays a role during DNA replication: acute degradation of Ki-67 in HCT116 cells causes severe delay of DNA replication, unloading of the replication machinery, DNA damage not sensed by canonical pathways (dependent on HUWE1 ligase), defects in sister chromatid cohesion, and activation of the cGAS/STING interferon response. APEX2 proteomics identified the replication machinery as a Ki-67 proximal interactor.","method":"Doxycycline-inducible E3 ligase + auxin-inducible degron (rapid acute depletion), APEX2 proximity proteomics, phospho-proteomics, DNA fiber assays, immunofluorescence in HCT116 cells","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — acute inducible depletion with multiple orthogonal readouts (proteomics, phospho-proteomics, replication assays, interferon response) in a single rigorous study","pmids":["38649976"],"is_preprint":false},{"year":2023,"finding":"CCDC86 (cyclon) is a novel Ki-67-interacting protein at the chromosome periphery. CCDC86 depletion causes partial disorganisation of the chromosome periphery with altered localisation of Ki-67 and nucleolin, formation of abnormal cytoplasmic aggregates, errors in chromosome alignment, altered spindle length, and increased apoptosis.","method":"RNA interference, co-immunoprecipitation/pulldown, immunofluorescence microscopy, biochemical fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying physical interaction plus siRNA phenotypic readout with multiple cellular endpoints, single lab","pmids":["36695333"],"is_preprint":false},{"year":2012,"finding":"IRF1 represses Ki-67 gene transcription in a dose-dependent manner by decreasing endogenous Sp1 protein levels (without affecting Sp1 mRNA), thereby interfering with Sp1 activation of the Ki-67 core promoter. Mutation of two functional Sp1 binding sites in the Ki-67 core promoter abrogated Sp1-dependent enhancement of Ki-67 promoter activity.","method":"Promoter-reporter assays, site-directed mutagenesis of Sp1 binding sites, transfection/overexpression of IRF1, Western blot and qPCR for Sp1 levels","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — promoter mutagenesis and reporter assay establish mechanism, but single lab with limited follow-up","pmids":["22890831"],"is_preprint":false},{"year":2000,"finding":"Ki-67 protein redistribution from the nuclear interior to the perichromosomal layer during mitosis is accompanied by posttranslational phosphorylation by cdc2 kinase and PKC.","method":"Phosphorylation assays, immunolocalization across cell cycle stages (review summarising experimental evidence from primary studies)","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cited as established in a review abstract without full experimental detail accessible; single method inference from primary work","pmids":["10837136"],"is_preprint":false},{"year":2004,"finding":"In early mouse embryos, Ki-67 protein shows cell-cycle-dependent redistribution: during mitosis it covers chromosome arms as part of the perichromosomal layer; in early G1 it distributes throughout the nucleus; for the remainder of interphase it associates with nucleolus precursor bodies (NPBs) or the nucleolus. This pattern is re-established after fertilization with a transition from minimal pronuclear expression to full somatic-type distribution by the 4-cell stage.","method":"Immunofluorescence and immunohistochemistry on staged mouse embryos across cell cycle phases","journal":"Cytogenetic and genome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct localization experiment but single method, no functional manipulation","pmids":["15237214"],"is_preprint":false}],"current_model":"Ki-67 (MKI67) is a large intrinsically disordered protein that (1) acts as a polymer surfactant on the mitotic chromosome periphery to prevent chromosome aggregation and enable independent chromosome motility; (2) organises the perichromosomal compartment by recruiting PP1 and multiple nucleolar proteins; (3) forms a Ki-67:PP1 holoenzyme via a novel PP1-binding mechanism regulated by Aurora B kinase to control mitotic exit phosphorylation; (4) mediates chromosome clustering during mitotic exit to exclude cytoplasmic ribosomes and re-establish nuclear compartmentalization; (5) associates with rDNA chromatin and the rRNA transcription machinery, suggesting a role in ribosomal RNA synthesis; (6) interacts with late-replicating genomic domains to influence heterochromatin organization and replication timing; (7) is required for normal DNA replication fork protection and genome stability, with its absence triggering HUWE1-dependent DNA damage and cGAS/STING-mediated interferon signalling; and (8) has its transcription repressed by IRF1 acting through reduction of Sp1 protein levels at the Ki-67 core promoter."},"narrative":{"mechanistic_narrative":"MKI67 (Ki-67) is a large intrinsically disordered protein that organizes the mitotic chromosome surface and coordinates nuclear reorganization across the cell cycle [PMID:27362226, PMID:24867636]. On the mitotic chromosome periphery it acts as a biological surfactant, using its size and net charge to form brush-like polymer arrangements that create a steric/electrostatic barrier preventing chromosome aggregation after nuclear envelope breakdown [PMID:27362226]. Ki-67 is the principal organizer of the perichromosomal compartment: its depletion abolishes association of nucleolar/periphery proteins—NIFK, B23/nucleophosmin, nucleolin and others—with the chromosome surface and eliminates the perichromosomal layer [PMID:24867636], and CCDC86/cyclon is a further periphery partner whose loss disorganizes this layer [PMID:36695333]. Ki-67 binds protein phosphatase 1 (PP1) through a novel pocket-engaging mechanism shared with RepoMan, discriminates among PP1 isoforms, and assembles a Ki-67:PP1 holoenzyme whose formation is dynamically controlled by Aurora B kinase during mitotic exit [PMID:27572260]. During mitotic exit the molecular brushes collapse to drive microtubule-independent chromosome clustering that physically excludes mature ribosomes and re-establishes nuclear-cytoplasmic compartmentalization [PMID:32879492]. Ki-67 maintains mitotic chromosome integrity cooperatively with but independently of condensins, which occupy the chromosome axis while Ki-67 coats the periphery [PMID:29487178]. Beyond mitosis, Ki-67 associates with rDNA chromatin and rRNA transcription machinery [PMID:16206250], engages large late-replicating genomic domains in competition with the nuclear lamina to control replication timing of (peri)centromeric regions [PMID:36245428], and is required for normal DNA replication—its acute degradation delays replication, unloads the replication machinery, triggers HUWE1-dependent DNA damage, sister chromatid cohesion defects, and cGAS/STING interferon signalling [PMID:38649976]. Ki-67 transcription is repressed by IRF1, which lowers Sp1 protein levels acting at the Ki-67 core promoter [PMID:22890831].","teleology":[{"year":2006,"claim":"Established the first direct genomic association of Ki-67, placing it at rDNA chromatin and rRNA transcription sites and implicating it in early steps of ribosomal RNA synthesis.","evidence":"ChIP and immunofluorescence co-localization with a novel antibody in proliferating and quiescent cells","pmids":["16206250"],"confidence":"Medium","gaps":["No demonstration that Ki-67 is functionally required for rRNA synthesis","Single lab without genetic perturbation of transcriptional output"]},{"year":2012,"claim":"Defined a transcriptional control mechanism for Ki-67, showing its promoter is governed by Sp1 and repressed by IRF1 via reduction of Sp1 protein.","evidence":"Promoter-reporter assays with Sp1-site mutagenesis and IRF1 overexpression in cell lines","pmids":["22890831"],"confidence":"Medium","gaps":["Mechanism by which IRF1 reduces Sp1 protein not resolved","Not validated at the endogenous chromatin level in vivo"]},{"year":2014,"claim":"Identified Ki-67 as a PP1-binding protein and the essential organizer of the perichromosomal compartment, explaining how the chromosome surface layer is built.","evidence":"siRNA depletion, CLEM, and co-immunoprecipitation in human cells","pmids":["24867636"],"confidence":"High","gaps":["Structural basis of PP1 binding not yet defined here","Functional consequence of periphery loss for downstream processes unresolved"]},{"year":2016,"claim":"Resolved the biophysical basis of Ki-67's chromosome-separation function, showing it behaves as a charged polymer surfactant whose activity depends on size and charge rather than a discrete catalytic domain.","evidence":"Truncation mutagenesis, fluorescence correlation spectroscopy, and dual-terminus live-cell imaging with mitotic readouts","pmids":["27362226"],"confidence":"High","gaps":["Does not address Ki-67 interphase functions","Identity of partners contributing to surface charge not enumerated"]},{"year":2016,"claim":"Provided the structural mechanism of Ki-67:PP1 holoenzyme assembly, revealing a novel PP1 pocket engagement shared with RepoMan and Aurora B-dependent regulation of mitotic exit phosphatase activity.","evidence":"Structural analysis, biochemical binding assays, and Aurora B kinase assays with mutagenesis","pmids":["27572260"],"confidence":"High","gaps":["In vivo substrates of the Ki-67:PP1 holoenzyme not fully mapped","Quantitative contribution to mitotic exit timing not measured"]},{"year":2018,"claim":"Distinguished Ki-67's contribution to chromosome architecture from that of condensins, showing peripheral and axial systems act independently but cooperatively.","evidence":"Auxin-inducible degron depletion of Ki-67 and SMC2 with epistasis readouts in HCT116 cells","pmids":["29487178"],"confidence":"High","gaps":["Molecular interface between periphery and axis not defined","Whether cooperation reflects physical or purely mechanical interaction unknown"]},{"year":2020,"claim":"Explained how Ki-67 contributes to nuclear reformation, showing brush collapse drives chromosome clustering that excludes ribosomes and re-establishes compartmentalization at mitotic exit.","evidence":"Live-cell imaging, depletion/rescue, and ribosome exclusion assays in HeLa cells","pmids":["32879492"],"confidence":"High","gaps":["Trigger for brush collapse not molecularly defined","Relationship to PP1-dependent dephosphorylation not directly linked"]},{"year":2022,"claim":"Mapped Ki-67's interphase genomic engagement, showing it binds late-replicating domains in competition with the lamina and controls replication timing of (peri)centromeric regions.","evidence":"pA-DamID genome-wide mapping, nucleolar perturbation, and replication timing assays in human cells","pmids":["36245428"],"confidence":"Medium","gaps":["No effect on chromatin-chromatin interactions detected, leaving organizational role narrow","Single-lab genome-wide approach"]},{"year":2023,"claim":"Extended the perichromosomal interactome by identifying CCDC86/cyclon as a Ki-67 partner required for proper periphery organization and faithful chromosome segregation.","evidence":"Co-IP/pulldown, RNAi, and immunofluorescence with multiple cellular endpoints","pmids":["36695333"],"confidence":"Medium","gaps":["Direct vs. indirect nature of the Ki-67-CCDC86 interaction not resolved","Single lab without reciprocal structural validation"]},{"year":2024,"claim":"Revealed an interphase requirement for Ki-67 in DNA replication and genome stability, linking its loss to replication delay, non-canonical DNA damage, and innate immune signalling.","evidence":"Acute inducible degradation, APEX2 proximity proteomics, phospho-proteomics, and DNA fiber assays in HCT116 cells","pmids":["38649976"],"confidence":"High","gaps":["Direct molecular role of Ki-67 at replication forks vs. proximal association unresolved","Mechanism connecting Ki-67 loss to HUWE1-dependent damage not defined"]},{"year":null,"claim":"How Ki-67's mitotic surfactant role mechanistically integrates with its interphase functions in rRNA synthesis, replication timing, and fork protection remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the disordered-polymer biophysics to replication-fork function","Substrate map of the Ki-67:PP1 holoenzyme incomplete","Whether interphase phenotypes derive from nucleolar organization or direct chromatin engagement unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5,6,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9]}],"complexes":["Ki-67:PP1 holoenzyme","perichromosomal layer/compartment"],"partners":["PPP1CA","NIFK","NPM1","NCL","CCDC86","SMC2","AURKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46013","full_name":"Proliferation marker protein Ki-67","aliases":["Antigen identified by monoclonal antibody Ki-67","Antigen KI-67","Antigen Ki67"],"length_aa":3256,"mass_kda":358.7,"function":"Protein that associates with the surface of mitotic chromosomes and acts both as a chromosome repellent during early mitosis and chromosome attractant during late mitosis (PubMed:27362226, PubMed:32879492, PubMed:35513709, PubMed:39153474). Required to maintain individual mitotic chromosomes dispersed in the cytoplasm following nuclear envelope disassembly (PubMed:27362226). During early mitosis, relocalizes from nucleoli to the chromosome surface where it forms extended brush structures that cover a substantial fraction of the chromosome surface (PubMed:27362226). The MKI67 brush structure prevents chromosomes from collapsing into a single chromatin mass by forming a steric and electrostatic charge barrier: the protein has a high net electrical charge and acts as a surfactant, dispersing chromosomes and enabling independent chromosome motility (PubMed:27362226). During mitotic anaphase, the MKI67 brush structure collapses and MKI67 switches from a chromosome repellent to a chromosome attractant to promote chromosome clustering and facilitate the exclusion of large cytoplasmic particles from the future nuclear space (PubMed:32879492, PubMed:39153474). Mechanistically, dephosphorylation during mitotic exit and simultaneous exposure of a conserved basic patch induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface, promoting coalescence of neighboring chromosome surfaces and clustering of chromosomes (PubMed:39153474). Binds premature ribosomal RNAs during anaphase; promoting liquid-liquid phase separation (PubMed:28935370, PubMed:39153474). Binds DNA, with a preference for supercoiled DNA and AT-rich DNA (PubMed:10878551). Does not contribute to the internal structure of mitotic chromosomes (By similarity). May play a role in chromatin organization; it is however unclear whether it plays a direct role in chromatin organization or whether it is an indirect consequence of its function in mitotic chromosome (PubMed:24867636)","subcellular_location":"Chromosome; Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P46013/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MKI67","classification":"Not Classified","n_dependent_lines":56,"n_total_lines":1208,"dependency_fraction":0.046357615894039736},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000148773","cell_line_id":"CID000719","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"chromatin","grade":2},{"compartment":"nuclear_punctae","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"H1F0","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HIST2H2BE;HIST1H2BB;HIST1H2BO;HIST1H2BJ","stoichiometry":0.2},{"gene":"POLR3B","stoichiometry":0.2},{"gene":"HIST1H2AJ;HIST1H2AH;HIST1H2AG;H2AFJ","stoichiometry":0.2},{"gene":"ZC3H11A","stoichiometry":0.2},{"gene":"ZNF512","stoichiometry":0.2},{"gene":"MMGT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000719","total_profiled":1310},"omim":[{"mim_id":"621490","title":"HYPOTRICHOSIS 16; HYPT16","url":"https://www.omim.org/entry/621490"},{"mim_id":"617569","title":"KINESIN FAMILY, MEMBER 15; KIF15","url":"https://www.omim.org/entry/617569"},{"mim_id":"616086","title":"SprT-LIKE N-TERMINAL DOMAIN PROTEIN; SPRTN","url":"https://www.omim.org/entry/616086"},{"mim_id":"614247","title":"MICRO RNA 519D; MIR519D","url":"https://www.omim.org/entry/614247"},{"mim_id":"611970","title":"NUCLEOLAR PROTEIN INTERACTING WITH THE FHA DOMAIN OF MKI67; NIFK","url":"https://www.omim.org/entry/611970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli rim","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":43.7},{"tissue":"lymphoid tissue","ntpm":49.0}],"url":"https://www.proteinatlas.org/search/MKI67"},"hgnc":{"alias_symbol":["MIB-1","PPP1R105","Ki-67"],"prev_symbol":[]},"alphafold":{"accession":"P46013","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46013","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MKI67","jax_strain_url":"https://www.jax.org/strain/search?query=MKI67"},"sequence":{"accession":"P46013","fasta_url":"https://rest.uniprot.org/uniprotkb/P46013.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46013/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46013"}},"corpus_meta":[{"pmid":"10653597","id":"PMC_10653597","title":"The Ki-67 protein: from the known and the unknown.","date":"2000","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10653597","citation_count":3487,"is_preprint":false},{"pmid":"29322240","id":"PMC_29322240","title":"Ki-67: more than a proliferation marker.","date":"2018","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/29322240","citation_count":685,"is_preprint":false},{"pmid":"11897369","id":"PMC_11897369","title":"The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.","date":"2002","source":"Journal of neuroscience methods","url":"https://pubmed.ncbi.nlm.nih.gov/11897369","citation_count":654,"is_preprint":false},{"pmid":"27362226","id":"PMC_27362226","title":"Ki-67 acts as a biological surfactant to disperse mitotic chromosomes.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27362226","citation_count":418,"is_preprint":false},{"pmid":"30653951","id":"PMC_30653951","title":"Ki-67 protein as a tumour proliferation marker.","date":"2019","source":"Clinica chimica acta; 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The chromosome separation function correlates with the size and net charge of the protein rather than a specific domain, suggesting a steric and electrostatic charge barrier mechanism. Fluorescence correlation spectroscopy demonstrated high surface density of Ki-67, and dual-colour labelling of both protein termini revealed an extended molecular conformation consistent with brush-like polymer surfactant arrangements.\",\n      \"method\": \"Truncation mutagenesis, fluorescence correlation spectroscopy, dual-colour live-cell imaging, siRNA depletion with mitotic phenotype readout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, FCS, live imaging) in a single rigorous study establishing the biophysical mechanism\",\n      \"pmids\": [\"27362226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ki-67 is a cell-cycle-regulated protein phosphatase 1 (PP1)-binding protein required for assembly of the perichromosomal compartment. siRNA depletion of Ki-67 causes failure of multiple nucleolar/periphery proteins (NIFK, B23/nucleophosmin, nucleolin, and four novel periphery proteins) to associate with the chromosome periphery, with CLEM showing near-complete loss of the perichromosomal layer. Ki-67 is also involved in phospho-regulation of B23/nucleophosmin.\",\n      \"method\": \"siRNA depletion, correlative light and electron microscopy (CLEM), co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying PP1 as binding partner, CLEM for ultrastructural validation, replicated by multiple downstream studies\",\n      \"pmids\": [\"24867636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ki-67 and RepoMan recruit protein phosphatase 1 (PP1) to form mitotic exit phosphatases via an identical, novel mechanism, interacting with a PP1 pocket not engaged by any other known PP1 regulator. Ki-67 distinguishes between distinct PP1 isoforms, and the assembly of the Ki-67:PP1 holoenzyme is dynamically regulated by Aurora B kinase during mitosis.\",\n      \"method\": \"Structural analysis (NMR/crystallography), biochemical binding assays, mutagenesis, kinase assays with Aurora B\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural and biochemical reconstitution with mutagenesis in a single detailed study\",\n      \"pmids\": [\"27572260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"During mitotic exit, Ki-67 molecular brushes collapse and promote chromosome clustering, which physically displaces large cytoplasmic components (including mature ribosomes) before nuclear envelope assembly, thereby re-establishing nuclear-cytoplasmic compartmentalization. This chromosome clustering function is microtubule-independent.\",\n      \"method\": \"Live-cell imaging, Ki-67 depletion/rescue, ribosome exclusion assays, HeLa cell manipulations\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistically dissected in two orthogonal readouts (chromosome clustering and ribosome exclusion) with genetic rescue, published in high-tier journal\",\n      \"pmids\": [\"32879492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ki-67 and condensins support the structural integrity of mitotic chromosomes through independent yet cooperative mechanisms: Ki-67 localizes to the chromosome periphery while condensins occupy the central axis, and their localization/dynamics are mutually independent. Combined depletion of Ki-67 and SMC2 (condensin core subunit) produces a severe phenotype (ball-like chromosome clusters with no thread-like structures) distinct from either single depletion.\",\n      \"method\": \"Auxin-inducible degron conditional degradation, immunofluorescence, live-cell imaging in HCT116 cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — auxin-inducible degron for acute protein depletion with clear epistasis readout, two orthogonal depletion combinations\",\n      \"pmids\": [\"29487178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ki-67 physically associates with chromatin at the promoter and transcribed regions of the ribosomal RNA (rRNA) gene cluster, and a fraction of Ki-67 co-localizes with the rRNA transcription machinery during interphase and mitosis in proliferating cells; Ki-67 can also be detected at rRNA synthesis sites in quiescent cells, suggesting a role in early steps of rRNA synthesis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), immunofluorescence co-localization, novel antibody (TuBB-9)\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP provides direct genomic association evidence; single lab, two orthogonal methods\",\n      \"pmids\": [\"16206250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"By pA-DamID genome-wide mapping, Ki-67 associates with large late-replicating genomic domains during early interphase on all chromosomes but shifts toward small chromosomes later in interphase as it is confined to nucleoli. Ki-67 does not detectably control chromatin-chromatin interactions during interphase but competes with the nuclear lamina for interaction with late-replicating DNA and controls replication timing of (peri)centromeric regions.\",\n      \"method\": \"pA-DamID genomic mapping, nucleolar perturbation experiments, replication timing assays in human cell lines\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide mapping with functional perturbation, single lab\",\n      \"pmids\": [\"36245428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ki-67 plays a role during DNA replication: acute degradation of Ki-67 in HCT116 cells causes severe delay of DNA replication, unloading of the replication machinery, DNA damage not sensed by canonical pathways (dependent on HUWE1 ligase), defects in sister chromatid cohesion, and activation of the cGAS/STING interferon response. APEX2 proteomics identified the replication machinery as a Ki-67 proximal interactor.\",\n      \"method\": \"Doxycycline-inducible E3 ligase + auxin-inducible degron (rapid acute depletion), APEX2 proximity proteomics, phospho-proteomics, DNA fiber assays, immunofluorescence in HCT116 cells\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — acute inducible depletion with multiple orthogonal readouts (proteomics, phospho-proteomics, replication assays, interferon response) in a single rigorous study\",\n      \"pmids\": [\"38649976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 (cyclon) is a novel Ki-67-interacting protein at the chromosome periphery. CCDC86 depletion causes partial disorganisation of the chromosome periphery with altered localisation of Ki-67 and nucleolin, formation of abnormal cytoplasmic aggregates, errors in chromosome alignment, altered spindle length, and increased apoptosis.\",\n      \"method\": \"RNA interference, co-immunoprecipitation/pulldown, immunofluorescence microscopy, biochemical fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying physical interaction plus siRNA phenotypic readout with multiple cellular endpoints, single lab\",\n      \"pmids\": [\"36695333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IRF1 represses Ki-67 gene transcription in a dose-dependent manner by decreasing endogenous Sp1 protein levels (without affecting Sp1 mRNA), thereby interfering with Sp1 activation of the Ki-67 core promoter. Mutation of two functional Sp1 binding sites in the Ki-67 core promoter abrogated Sp1-dependent enhancement of Ki-67 promoter activity.\",\n      \"method\": \"Promoter-reporter assays, site-directed mutagenesis of Sp1 binding sites, transfection/overexpression of IRF1, Western blot and qPCR for Sp1 levels\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — promoter mutagenesis and reporter assay establish mechanism, but single lab with limited follow-up\",\n      \"pmids\": [\"22890831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ki-67 protein redistribution from the nuclear interior to the perichromosomal layer during mitosis is accompanied by posttranslational phosphorylation by cdc2 kinase and PKC.\",\n      \"method\": \"Phosphorylation assays, immunolocalization across cell cycle stages (review summarising experimental evidence from primary studies)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cited as established in a review abstract without full experimental detail accessible; single method inference from primary work\",\n      \"pmids\": [\"10837136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In early mouse embryos, Ki-67 protein shows cell-cycle-dependent redistribution: during mitosis it covers chromosome arms as part of the perichromosomal layer; in early G1 it distributes throughout the nucleus; for the remainder of interphase it associates with nucleolus precursor bodies (NPBs) or the nucleolus. This pattern is re-established after fertilization with a transition from minimal pronuclear expression to full somatic-type distribution by the 4-cell stage.\",\n      \"method\": \"Immunofluorescence and immunohistochemistry on staged mouse embryos across cell cycle phases\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct localization experiment but single method, no functional manipulation\",\n      \"pmids\": [\"15237214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Ki-67 (MKI67) is a large intrinsically disordered protein that (1) acts as a polymer surfactant on the mitotic chromosome periphery to prevent chromosome aggregation and enable independent chromosome motility; (2) organises the perichromosomal compartment by recruiting PP1 and multiple nucleolar proteins; (3) forms a Ki-67:PP1 holoenzyme via a novel PP1-binding mechanism regulated by Aurora B kinase to control mitotic exit phosphorylation; (4) mediates chromosome clustering during mitotic exit to exclude cytoplasmic ribosomes and re-establish nuclear compartmentalization; (5) associates with rDNA chromatin and the rRNA transcription machinery, suggesting a role in ribosomal RNA synthesis; (6) interacts with late-replicating genomic domains to influence heterochromatin organization and replication timing; (7) is required for normal DNA replication fork protection and genome stability, with its absence triggering HUWE1-dependent DNA damage and cGAS/STING-mediated interferon signalling; and (8) has its transcription repressed by IRF1 acting through reduction of Sp1 protein levels at the Ki-67 core promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MKI67 (Ki-67) is a large intrinsically disordered protein that organizes the mitotic chromosome surface and coordinates nuclear reorganization across the cell cycle [#0, #1]. On the mitotic chromosome periphery it acts as a biological surfactant, using its size and net charge to form brush-like polymer arrangements that create a steric/electrostatic barrier preventing chromosome aggregation after nuclear envelope breakdown [#0]. Ki-67 is the principal organizer of the perichromosomal compartment: its depletion abolishes association of nucleolar/periphery proteins—NIFK, B23/nucleophosmin, nucleolin and others—with the chromosome surface and eliminates the perichromosomal layer [#1], and CCDC86/cyclon is a further periphery partner whose loss disorganizes this layer [#8]. Ki-67 binds protein phosphatase 1 (PP1) through a novel pocket-engaging mechanism shared with RepoMan, discriminates among PP1 isoforms, and assembles a Ki-67:PP1 holoenzyme whose formation is dynamically controlled by Aurora B kinase during mitotic exit [#2]. During mitotic exit the molecular brushes collapse to drive microtubule-independent chromosome clustering that physically excludes mature ribosomes and re-establishes nuclear-cytoplasmic compartmentalization [#3]. Ki-67 maintains mitotic chromosome integrity cooperatively with but independently of condensins, which occupy the chromosome axis while Ki-67 coats the periphery [#4]. Beyond mitosis, Ki-67 associates with rDNA chromatin and rRNA transcription machinery [#5], engages large late-replicating genomic domains in competition with the nuclear lamina to control replication timing of (peri)centromeric regions [#6], and is required for normal DNA replication—its acute degradation delays replication, unloads the replication machinery, triggers HUWE1-dependent DNA damage, sister chromatid cohesion defects, and cGAS/STING interferon signalling [#7]. Ki-67 transcription is repressed by IRF1, which lowers Sp1 protein levels acting at the Ki-67 core promoter [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first direct genomic association of Ki-67, placing it at rDNA chromatin and rRNA transcription sites and implicating it in early steps of ribosomal RNA synthesis.\",\n      \"evidence\": \"ChIP and immunofluorescence co-localization with a novel antibody in proliferating and quiescent cells\",\n      \"pmids\": [\"16206250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration that Ki-67 is functionally required for rRNA synthesis\", \"Single lab without genetic perturbation of transcriptional output\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a transcriptional control mechanism for Ki-67, showing its promoter is governed by Sp1 and repressed by IRF1 via reduction of Sp1 protein.\",\n      \"evidence\": \"Promoter-reporter assays with Sp1-site mutagenesis and IRF1 overexpression in cell lines\",\n      \"pmids\": [\"22890831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IRF1 reduces Sp1 protein not resolved\", \"Not validated at the endogenous chromatin level in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Ki-67 as a PP1-binding protein and the essential organizer of the perichromosomal compartment, explaining how the chromosome surface layer is built.\",\n      \"evidence\": \"siRNA depletion, CLEM, and co-immunoprecipitation in human cells\",\n      \"pmids\": [\"24867636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PP1 binding not yet defined here\", \"Functional consequence of periphery loss for downstream processes unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the biophysical basis of Ki-67's chromosome-separation function, showing it behaves as a charged polymer surfactant whose activity depends on size and charge rather than a discrete catalytic domain.\",\n      \"evidence\": \"Truncation mutagenesis, fluorescence correlation spectroscopy, and dual-terminus live-cell imaging with mitotic readouts\",\n      \"pmids\": [\"27362226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address Ki-67 interphase functions\", \"Identity of partners contributing to surface charge not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural mechanism of Ki-67:PP1 holoenzyme assembly, revealing a novel PP1 pocket engagement shared with RepoMan and Aurora B-dependent regulation of mitotic exit phosphatase activity.\",\n      \"evidence\": \"Structural analysis, biochemical binding assays, and Aurora B kinase assays with mutagenesis\",\n      \"pmids\": [\"27572260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrates of the Ki-67:PP1 holoenzyme not fully mapped\", \"Quantitative contribution to mitotic exit timing not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished Ki-67's contribution to chromosome architecture from that of condensins, showing peripheral and axial systems act independently but cooperatively.\",\n      \"evidence\": \"Auxin-inducible degron depletion of Ki-67 and SMC2 with epistasis readouts in HCT116 cells\",\n      \"pmids\": [\"29487178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface between periphery and axis not defined\", \"Whether cooperation reflects physical or purely mechanical interaction unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Explained how Ki-67 contributes to nuclear reformation, showing brush collapse drives chromosome clustering that excludes ribosomes and re-establishes compartmentalization at mitotic exit.\",\n      \"evidence\": \"Live-cell imaging, depletion/rescue, and ribosome exclusion assays in HeLa cells\",\n      \"pmids\": [\"32879492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for brush collapse not molecularly defined\", \"Relationship to PP1-dependent dephosphorylation not directly linked\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped Ki-67's interphase genomic engagement, showing it binds late-replicating domains in competition with the lamina and controls replication timing of (peri)centromeric regions.\",\n      \"evidence\": \"pA-DamID genome-wide mapping, nucleolar perturbation, and replication timing assays in human cells\",\n      \"pmids\": [\"36245428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No effect on chromatin-chromatin interactions detected, leaving organizational role narrow\", \"Single-lab genome-wide approach\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the perichromosomal interactome by identifying CCDC86/cyclon as a Ki-67 partner required for proper periphery organization and faithful chromosome segregation.\",\n      \"evidence\": \"Co-IP/pulldown, RNAi, and immunofluorescence with multiple cellular endpoints\",\n      \"pmids\": [\"36695333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of the Ki-67-CCDC86 interaction not resolved\", \"Single lab without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an interphase requirement for Ki-67 in DNA replication and genome stability, linking its loss to replication delay, non-canonical DNA damage, and innate immune signalling.\",\n      \"evidence\": \"Acute inducible degradation, APEX2 proximity proteomics, phospho-proteomics, and DNA fiber assays in HCT116 cells\",\n      \"pmids\": [\"38649976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular role of Ki-67 at replication forks vs. proximal association unresolved\", \"Mechanism connecting Ki-67 loss to HUWE1-dependent damage not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Ki-67's mitotic surfactant role mechanistically integrates with its interphase functions in rRNA synthesis, replication timing, and fork protection remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the disordered-polymer biophysics to replication-fork function\", \"Substrate map of the Ki-67:PP1 holoenzyme incomplete\", \"Whether interphase phenotypes derive from nucleolar organization or direct chromatin engagement unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5, 6, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"Ki-67:PP1 holoenzyme\", \"perichromosomal layer/compartment\"],\n    \"partners\": [\"PPP1CA\", \"NIFK\", \"NPM1\", \"NCL\", \"CCDC86\", \"SMC2\", \"AURKB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}