{"gene":"CENPF","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1995,"finding":"CENP-F is a nuclear matrix protein that accumulates during the cell cycle, peaks at G2/M, localizes to kinetochore plates (outer surface of outer kinetochore plate) from late G2 through early anaphase, then redistributes to the spindle midzone and midbody, and is rapidly degraded after mitosis. The predicted structure consists of two ~1,600-amino acid coiled-coil domains flanking a central flexible core, with a putative P-loop nucleotide binding site (ADIPTGKT) in the globular C-terminus.","method":"cDNA cloning, immunofluorescence across cell cycle stages, immunoelectron microscopy, nuclease digestion, cell fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IF, IEM, biochemical fractionation), foundational characterization replicated in subsequent studies","pmids":["7542657"],"is_preprint":false},{"year":1993,"finding":"CENP-F associates with kinetochores independent of tubulin, and its dissociation from kinetochores is dependent on events connected with the onset of anaphase. CENP-F localizes to the outer surface of the outer kinetochore plate.","method":"Immunofluorescence with affinity-purified antibodies, immune depletion experiments, indirect immunofluorescence on HeLa cells","journal":"Cell motility and the cytoskeleton","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cytological and biochemical experiments, replicated by subsequent studies","pmids":["7904902"],"is_preprint":false},{"year":2000,"finding":"CENP-F is farnesylated in tumor cells (DLD-1): peptides from the COOH-terminal CAAX box of CENP-F are substrates for farnesyl transferase but not geranylgeranyl transferase-I, and prenylation is completely inhibited by the farnesyl transferase inhibitor SCH 66336. Preventing farnesylation does not affect kinetochore localization of CENP-F but alters the association between CENP-E and microtubules.","method":"In vitro farnesyl transferase substrate assay, metabolic labeling in DLD-1 cells, immunohistochemistry with FTI treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic substrate assay plus cell-based validation, independently confirmed by multiple subsequent studies","pmids":["10852915"],"is_preprint":false},{"year":2002,"finding":"Farnesylation of CENP-F is required for its localization to the nuclear envelope at G2/M and to kinetochores in prometaphase, for timely G2/M progression, and for CENP-F degradation after mitosis. Ectopic expression of the kinetochore targeting domain delays G2/M progression in a CAAX motif-dependent manner.","method":"Ectopic expression of CENP-F kinetochore targeting domain with CAAX mutation, farnesyl transferase inhibitor treatment, immunofluorescence localization, cell cycle analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — CAAX mutagenesis combined with FTI treatment and localization readouts, replicated in multiple subsequent studies","pmids":["12154071"],"is_preprint":false},{"year":1998,"finding":"CENP-F directly interacts with CENP-E (via yeast two-hybrid using CENP-E kinetochore binding domain as bait) and assembles onto kinetochores sequentially after CENP-E. CENP-F, BubR1, and CENP-E define discrete steps along the kinetochore assembly pathway.","method":"Yeast two-hybrid screen using CENP-E kinetochore binding domain, immunofluorescence co-localization, sequential kinetochore assembly analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid interaction, supported by co-localization data and assembly-order observations across multiple labs","pmids":["9763420"],"is_preprint":false},{"year":2004,"finding":"Bub1 is required for kinetochore localization of CENP-F (as well as BubR1, Cenp-E, and Mad2) in human somatic cells; RNAi-mediated depletion of Bub1 prevents subsequent CENP-F kinetochore assembly.","method":"RNA interference (RNAi) depletion of Bub1 in human cells, immunofluorescence to assess kinetochore localization of CENP-F and other checkpoint proteins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi epistasis with direct localization readout, replicated independently","pmids":["15020684"],"is_preprint":false},{"year":2003,"finding":"CENP-I (a constitutive kinetochore protein) is required for kinetochore localization of CENP-F and checkpoint proteins MAD1 and MAD2; depletion of CENP-I causes G2 delay and prevents mitotic arrest.","method":"RNAi depletion of CENP-I, immunofluorescence for CENP-F and checkpoint protein localization, cell cycle analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi epistasis with direct localization phenotype, published in high-impact journal with rigorous controls","pmids":["12640463"],"is_preprint":false},{"year":2005,"finding":"In C. elegans, HCP-1/2 (CENP-F orthologs) physically associate with CLASP (CLS-2) and are required for its kinetochore localization; CLASP depletion does not prevent HCP-1/2 targeting. The key role of HCP-1/2 is to target CLASP to kinetochores to promote microtubule polymerization at kinetochore-bound microtubules and ensure sister-chromatid biorientation.","method":"Biochemical purification, co-immunoprecipitation, RNAi depletion, immunofluorescence localization in C. elegans embryos, genetic epistasis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical purification plus epistatic RNAi with direct localization readout, replicated with multiple orthogonal methods","pmids":["15854912"],"is_preprint":false},{"year":2005,"finding":"CENP-F depletion by RNAi causes reduced stability of kinetochore microtubules, reduced tension between sister kinetochores of aligned chromosomes, merotelic associations, and continuous or intermittent Mad1 recruitment ('twinkling') indicating cycles of spindle checkpoint reactivation and silencing. A subset of CENP-F-depleted cells show complete failure of kinetochore assembly.","method":"RNAi depletion, live-cell imaging with YFP-Mad1, inter-kinetochore distance measurements, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging combined with RNAi and quantitative functional readouts","pmids":["16252009"],"is_preprint":false},{"year":2005,"finding":"CENP-F RNAi causes failure of metaphase chromosome alignment, anaphase segregation, and cytokinesis; kinetochores can still attach microtubules but oscillatory movements and inter-kinetochore distances are severely reduced. CENP-F depletion also causes premature loss of centromeric chromatid cohesion. The prolonged mitosis induced by CENP-F RNAi is dependent on the spindle checkpoint kinase BubR1.","method":"RNAi, immunofluorescence, live-cell imaging, epistasis with BubR1 RNAi","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts with RNAi, clear epistasis established","pmids":["16219694"],"is_preprint":false},{"year":2006,"finding":"CENP-F is a novel microtubule-binding protein with two microtubule-binding domains at opposite ends of the molecule; the C-terminal microtubule-binding domain stimulates microtubule polymerization in vitro. CENP-F depletion causes cells to exit mitosis despite defective kinetochore attachments and reduces kinetochore levels of Mad1, Mad2, hBUBR1, hBUB1, and hMps1.","method":"In vitro microtubule binding and polymerization assays with purified CENP-F domains, RNAi depletion, immunofluorescence quantification of checkpoint proteins","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro microtubule binding and polymerization reconstitution assay plus cell-based RNAi phenotypic analysis","pmids":["16601978"],"is_preprint":false},{"year":2007,"finding":"CENP-F directly interacts with Ndel1 and Nde1 (NudE-related proteins), and is required for kinetochore localization of Ndel1, Nde1, and Lis1. Nde1 (but not Ndel1) is required for kinetochore localization of dynein. CENP-F thus links the Ndel1/Nde1/Lis1/dynein pathway to kinetochores.","method":"Co-immunoprecipitation, RNAi depletion of CENP-F, Nde1, and Ndel1, immunofluorescence for localization, chromosome alignment assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus epistatic RNAi with direct localization readouts, clear pathway hierarchy established","pmids":["17600710"],"is_preprint":false},{"year":2009,"finding":"CENP-F localizes to the centrosome and interacts with Hook2 (a centrosomal linker protein) via yeast two-hybrid and co-immunoprecipitation. Loss of CENP-F in CENP-F(-/-) cells eliminates centrosome-specific microtubule repolymerization after nocodazole treatment, but MT repolymerization from the Golgi is unaffected, indicating CENP-F regulates centrosomal MT nucleation and anchoring.","method":"Yeast two-hybrid screen, co-immunoprecipitation, CENP-F(-/-) MEFs, microtubule repolymerization assay after nocodazole washout, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by co-IP, genetic KO model with specific functional assay","pmids":["19793914"],"is_preprint":false},{"year":2008,"finding":"Murine CENP-F interacts with syntaxin 4 (a SNARE complex component) via yeast two-hybrid and co-immunoprecipitation. Endogenous CENP-F forms a complex with syntaxin 4, SNAP-25, and VAMP2. CENP-F depletion disrupts GLUT4 trafficking, and dominant-negative CENP-F inhibits cell coupling, demonstrating a role in vesicular transport through linking the SNARE system to the microtubule network.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal colocalization, RNAi depletion, dominant-negative expression, GLUT4 trafficking assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by co-IP with endogenous proteins, loss-of-function with specific trafficking readout","pmids":["18827011"],"is_preprint":false},{"year":2013,"finding":"The N-terminal microtubule-binding domain of CENP-F binds microtubules with affinity similar to the Ndc80 complex, while the C-terminal domain shows much lower affinity. EM analysis reveals both domains engage the microtubule surface in a disordered manner with no favored binding geometry, suggesting they may facilitate initial lateral attachments.","method":"Biochemical microtubule binding assays (cosedimentation), electron microscopy of domain-microtubule complexes","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical reconstitution with structural (EM) validation, single lab","pmids":["23892111"],"is_preprint":false},{"year":2015,"finding":"CENP-F interacts directly with the mitochondrial protein Miro in a cell cycle-dependent manner. Cenp-F is recruited to mitochondria by Miro at the time of cytokinesis and associates with microtubule growing tips. Loss of CENP-F or Miro decreases spreading of the mitochondrial network and causes cytokinesis-specific defects in mitochondrial transport toward the cell periphery.","method":"Co-immunoprecipitation, live-cell imaging, RNAi depletion of CENP-F and Miro, quantitative mitochondrial distribution analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct co-IP interaction confirmed, live imaging with loss-of-function showing specific mitochondrial transport defect","pmids":["26259702"],"is_preprint":false},{"year":2017,"finding":"CENP-F tracks growing microtubule ends in living cells. In vitro reconstitution demonstrates that microtubule tips can transport CENP-F-coated artificial cargoes over micrometer-long distances during both growing and shrinking phases, establishing CENP-F as a tip-tracking transporter for mitochondria and other cargoes.","method":"Live-cell imaging of CENP-F tracking, in vitro reconstitution assay with CENP-F-coated beads and dynamic microtubules","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of tip-tracking plus live-cell imaging confirmation","pmids":["28701340"],"is_preprint":false},{"year":2017,"finding":"CENP-F contains a bipartite classical nuclear localization signal (cNLS) with three Cdk1 phosphorylation sites. Phosphomimetic mutations at these sites strongly reduce the interaction between the CENP-F cNLS and karyopherin α (importin α), and diminish nuclear localization. Cdk1-mediated phosphorylation of the cNLS in G2 phase thus regulates CENP-F nuclear export, enabling its cytoplasmic functions.","method":"Identification and mutagenesis of cNLS phosphorylation sites, binding assay between cNLS peptides and karyopherin α, cell localization assay with phosphomimetic mutants","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding assay with mutagenesis plus cellular localization validation, single lab","pmids":["28723232"],"is_preprint":false},{"year":2018,"finding":"CENP-F directly and specifically interacts with BUB1 (but not BUBR1), whereas CENP-E directly interacts with BUBR1 (but not BUB1). The CENP-F/BUB1 interaction requires a dimeric coiled-coil in CENP-F and the kinase domain of BUB1, established by biochemical reconstitution. BUB1 is stringently required for CENP-F kinetochore localization while BUBR1 is dispensable for CENP-E localization. Both are recruited to kinetochores independently of the RZZ complex.","method":"Biochemical reconstitution of direct interactions, mutagenesis of binding determinants, RNAi depletion of BUB1/BUBR1 with immunofluorescence localization readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with mutagenesis plus cell-based epistasis, clear specificity established","pmids":["29748388"],"is_preprint":false},{"year":2018,"finding":"The Cenp-F C-terminal region contains separate binding sites for Nup133 and Bub1. Nup133 interacts with a conserved helix within its β-propeller and a short leucine zipper-containing dimeric segment of Cenp-F, mediating localization to nuclear pores in prophase. A point mutation in an adjacent leucine zipper impairs Bub1 interaction and kinetochore targeting of the Cenp-F KT-core domain without affecting Nup133 binding. Cenp-E redundantly contributes with Bub1 to Cenp-F kinetochore recruitment.","method":"In silico structural modeling, yeast two-hybrid assays, structure-guided mutagenesis, immunofluorescence localization of mutants","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid with structure-guided mutagenesis separating two distinct binding interfaces, confirmed by cellular localization","pmids":["29632243"],"is_preprint":false},{"year":2020,"finding":"CENP-F contains two microtubule-binding domains that make distinct contributions: they stabilize kinetochore-microtubule attachments and contribute to force transduction but are dispensable for chromosome congression. A specialized domain interacts directly with Nde1 to limit dynein-mediated stripping of corona cargoes; this antagonistic activity is crucial for maintaining corona composition and ensuring efficient kinetochore biorientation.","method":"CRISPR gene editing, engineered separation-of-function mutants, live-cell imaging, quantitative kinetochore attachment analysis, co-immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR separation-of-function mutants with multiple orthogonal functional readouts and direct interaction evidence","pmids":["32207772"],"is_preprint":false},{"year":2011,"finding":"Rab5 (a small GTPase that regulates vesicular trafficking) forms a complex with a subset of CENP-F in mitotic cells and regulates the kinetics of CENP-F release from the nuclear envelope and its accumulation on kinetochores. Simultaneous depletion of both Rab5 and CENP-F recapitulates the individual depletion mitotic defects, indicating epistatic roles for these two proteins in chromosome congression.","method":"RNAi, co-immunoprecipitation of Rab5 and CENP-F from mitotic cells, immunofluorescence, double-depletion epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus epistatic RNAi, single lab, mechanistic details of the complex not fully resolved","pmids":["21987812"],"is_preprint":false},{"year":2010,"finding":"Both the amino and carboxy termini of KSHV LANA bind to CENP-F, and LANA co-localizes with CENP-F at centromeric regions. LANA also associates with Bub1, which forms a complex with CENP-F. FISH demonstrates co-localization of Bub1, LANA, and KSHV episome tethered to host chromosome. Knockdown of Bub1 (but not CENP-F) dramatically reduces KSHV genome copy number, suggesting the LANA-CENP-F/Bub1 interaction contributes to viral genome persistence.","method":"Co-immunoprecipitation, immunofluorescence co-localization, FISH, shRNA knockdown of Bub1 and CENP-F with genome copy number quantification","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction with functional validation by knockdown, but CENP-F knockdown showed no dramatic effect on genome maintenance","pmids":["20660191"],"is_preprint":false},{"year":2015,"finding":"CENP-F co-localizes with Ninein at the subdistal appendages of the mother centriole and co-immunoprecipitates with IFT88 from mitotic and serum-starved HEK293 cells. Mutations in CENPF cause ciliopathy with truncated cilia and failure of IFT88 to co-localize with CENP-F along ciliary axonemes, establishing a role for CENP-F in ciliogenesis.","method":"Whole exome sequencing, co-immunoprecipitation of CENP-F with IFT88, immunofluorescence co-localization in renal epithelial cells, analysis of patient tissue with CENPF mutations","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction, patient tissue showing loss-of-function ciliary phenotype, single lab","pmids":["25564561"],"is_preprint":false},{"year":2010,"finding":"RNAi depletion of CENP-F markedly downregulates methylation of histone H3 at K4 and K9, and decreases association of HP1α with mitotic chromosomes, revealing a role for CENP-F in regulating epigenetic histone H3 modifications.","method":"RNAi, immunofluorescence for H3K4me and H3K9me, HP1α localization analysis","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RNAi + IF), no direct biochemical mechanism established for how CENP-F influences methyltransferase activity","pmids":["20213041"],"is_preprint":false},{"year":2010,"finding":"Overexpression of C-terminal CENP-F deletion mutants induces interphase chromatin condensation into aggregates. CENP-F associates with DNA-dependent protein kinase (DNA-PK) by co-immunoprecipitation, and the DNA-PK association activity of CENP-F mutants correlates with their ability to induce chromatin aggregation.","method":"Overexpression of truncation mutants, co-immunoprecipitation with DNA-PK, in situ hybridization with chromosome painting probes","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, overexpression artifacts possible, single lab with no functional validation beyond correlation","pmids":["20978035"],"is_preprint":false},{"year":2012,"finding":"Cardiac-specific deletion of CENP-F in murine cardiomyocytes causes decreased cell division, blunted trabeculation, disruption of intercalated discs, loss of microtubule integrity at the costamere, and 100% development of progressive dilated cardiomyopathy with heart block and scarring, establishing a direct genetic link between CENP-F loss and cardiomyopathy.","method":"Cre-loxP conditional knockout in murine cardiomyocytes, histology, immunofluorescence for microtubule and intercalated disc components, cardiac functional analysis","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional genetic KO with defined cellular and organ-level phenotypes, multiple readouts","pmids":["22563055"],"is_preprint":false},{"year":2016,"finding":"CENP-F(-/-) mouse embryonic fibroblasts show severely diminished microtubule dynamics during interphase, which underlies defects in cell migration, focal adhesion dynamics, and primary cilia formation, demonstrating CENP-F regulates MT dynamics and heterogeneous cellular functions outside of cell division.","method":"Genetic deletion model (CENP-F(-/-) MEFs), live-cell microtubule dynamics imaging, cell migration assays, immunofluorescence for focal adhesions and cilia","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal functional readouts in interphase cells","pmids":["27146114"],"is_preprint":false},{"year":2019,"finding":"Miro-deficient CENP-F point mutant (deficient in Miro binding) causes a defect in mitochondrial spreading in cultured cells similar to Miro depletion. Mice with this mutation or truncations lacking the farnesylated C-terminus develop normally, indicating the Miro-dependent mitochondrial pool of CENP-F and its farnesylated C-terminus are dispensable for normal murine development.","method":"CRISPR/Cas9-engineered CENP-F point mutation abolishing Miro binding, mouse knock-in models, live-cell mitochondrial distribution imaging","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR separation-of-function mutation with in vivo mouse model and specific functional readout","pmids":["30856164"],"is_preprint":false},{"year":2025,"finding":"Importin beta generates proximity ligation products with CENP-F during mitosis. Importin beta overexpression alters CENP-F mitotic localization (promoting accumulation at spindle poles and decreasing kinetochore association) and causes persistence of CENP-F into late mitosis when it normally disappears, in a process requiring microtubule integrity. This implicates importin beta in the spatial and temporal control of CENP-F during mitosis and reveals a protective role of microtubules against premature CENP-F ubiquitination.","method":"Proximity ligation assay, importin beta overexpression, immunofluorescence, microtubule depolymerization experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proximity ligation (not classical co-IP) plus functional overexpression with localization readout, single lab","pmids":["40596417"],"is_preprint":false},{"year":2025,"finding":"USP4 interacts with and stabilizes CENP-F via deubiquitination. CENP-F undergoes degradation via the ubiquitination-proteasome pathway in colorectal cancer cells. Clinical samples confirm that USP4 expression positively correlates with CENP-F protein but not mRNA levels, establishing USP4 as a deubiquitinase that controls CENP-F stability.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, Western blot for protein levels, clinical sample correlation analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction, mechanistic link to ubiquitin-proteasome pathway validated in cells and clinical samples, single lab","pmids":["39922805"],"is_preprint":false},{"year":2025,"finding":"SETDB1-PC4-UPF1 constitutes a post-transcriptional machinery that controls periodic degradation of CENPF mRNA. In early G2, newly synthesized CENPF mRNAs bind to PC4; SETDB1 then dimethylates PC4 at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of CENPF mRNAs.","method":"RNA immunoprecipitation, protein interaction assays, methylation assays, mRNA stability assays, cell cycle synchronization","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical mechanism of mRNA regulation established with multiple components, single lab","pmids":["40016337"],"is_preprint":false},{"year":2023,"finding":"CENPF mRNA is subject to N6-methyladenosine (m6A) modification mediated by METTL3. This modification is recognized by HNRNPA2B1, which promotes CENPF mRNA stability. CENPF binds FAK and promotes its cytoplasmic localization; the metastatic function of CENPF is dependent on the MAPK signaling pathway.","method":"MeRIP-seq, RNA immunoprecipitation-qPCR, RNA pulldown, co-immunoprecipitation, mass spectrometry, immunofluorescence, gain/loss-of-function experiments","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods for m6A and HNRNPA2B1 interaction; CENPF-FAK co-IP established, single lab","pmids":["37256823"],"is_preprint":false},{"year":2024,"finding":"CENP-F functions with FOXM1 to co-regulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in altered chromatin accessibility at G2/M genes and reduced FOXM1-MBB complex formation. This FOXM1-CENP-F transcriptional co-regulation is cancer-specific and involves CENP-F acting as an outer kinetochore component that also has a nuclear transcriptional role.","method":"CRISPR loss-of-function, ATAC-seq (chromatin accessibility), ChIP, co-immunoprecipitation for FOXM1-MBB complex, chromosome segregation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with chromatin accessibility and protein complex readouts, single lab with multiple methods","pmids":["38779933"],"is_preprint":false},{"year":2003,"finding":"DNA damage-induced G2 arrest in HeLa cells (TP53-independent) occurs in early G2, before redistribution of CENP-F to the nuclear envelope and kinetochores and before chromosome condensation commences, using CENP-F localization as a precise cell cycle marker to define the arrest point.","method":"DNA damage treatment, immunofluorescence for CENP-F localization as a G2 stage marker, cell cycle analysis","journal":"Radiation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CENP-F used as stage-specific marker to define G2 arrest point; establishes CENP-F nuclear envelope/kinetochore translocation as a late-G2 landmark","pmids":["12710871"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, BUB-1, HCP-1/2 (CENP-F orthologs), and CLS-2 (CLASP) form a BHC kinetochore module that synergistically stabilizes microtubules and promotes microtubule pause. BUB-1 and HCP-1/2 do not only act as targeting factors for CLS-2 but also actively participate in controlling kinetochore-microtubule dynamics to promote meiotic spindle formation and accurate chromosome segregation.","method":"In vivo structure-function analysis with RNAi/mutations, in vitro microtubule stabilization and pause assays, live imaging","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro microtubule assays combined with in vivo structure-function analysis showing synergistic activity, multiple orthogonal methods","pmids":["36799894"],"is_preprint":false},{"year":2023,"finding":"CENPF targets Chk1-mediated G2/M phase arrest and binds to Rb to compete with E2F1 in triple-negative breast cancer cells; this competition at the Rb-E2F1 axis modulates the DNA damage response.","method":"Co-immunoprecipitation of CENPF with Rb, ChIP, siRNA knockdown, cell cycle analysis","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP for CENPF-Rb interaction, no reconstitution, single lab","pmids":["36720923"],"is_preprint":false},{"year":2025,"finding":"CENPF interacts with PLA2G4A by co-immunoprecipitation and molecular docking. Silencing CENPF reduces mTORC1 signaling and EMT in glioma cells; the CENPF-PLA2G4A interaction promotes downstream oncogenic signaling. Combined silencing of CENPF and a PLA2G4A inhibitor shows synergistic anti-glioma effects.","method":"Molecular docking, co-immunoprecipitation, siRNA knockdown, Western blot for mTORC1 pathway, cell proliferation and invasion assays","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP confirmed interaction, but downstream mechanistic details rely largely on pathway inhibitor experiments, single lab","pmids":["40025532"],"is_preprint":false}],"current_model":"CENP-F is a large (~367 kDa) farnesylated nuclear matrix protein that accumulates during S/G2, undergoes Cdk1-dependent nuclear export in G2 via phosphorylation of its bipartite NLS (weakening karyopherin α binding), localizes to the nuclear envelope (via Nup133 interaction) and then to kinetochores (via direct interaction with BUB1) from late G2 through anaphase, where it recruits the Ndel1/Nde1/Lis1/dynein pathway and CLASP to kinetochores, stabilizes kinetochore-microtubule attachments through two microtubule-binding domains, limits dynein-mediated corona stripping via Nde1, and is degraded after mitosis in a farnesylation- and microtubule/importin-beta-dependent manner; outside of mitosis, CENP-F also tracks dynamic microtubule tips to transport mitochondria (via Miro interaction), regulates centrosomal microtubule nucleation (via Hook2 interaction), participates in vesicular transport (via syntaxin 4/SNARE association), co-regulates G2/M transcription with FOXM1, and loss-of-function causes cardiomyopathy, ciliopathy (Strømme syndrome), and early embryonic lethality."},"narrative":{"mechanistic_narrative":"CENP-F is a large, cell-cycle-regulated nuclear matrix protein that functions as a multivalent microtubule-associated scaffold, accumulating during S/G2 and peaking at G2/M before being rapidly degraded after mitosis [PMID:7542657]. Its mitotic role centers on the outer kinetochore: it loads onto kinetochores from late G2 through early anaphase downstream of constitutive and checkpoint components, requiring CENP-I and BUB1, with which it forms a direct, biochemically reconstituted complex via a CENP-F coiled-coil and the BUB1 kinase domain [PMID:7904902, PMID:15020684, PMID:12640463, PMID:29748388]. A separate C-terminal interface engages the nucleoporin Nup133 to drive nuclear-envelope/pore localization in prophase, while the adjacent BUB1-binding element targets the kinetochore-core domain [PMID:29632243]. At kinetochores CENP-F serves as a recruitment hub, linking the Ndel1/Nde1/Lis1/dynein pathway and CLASP to the kinetochore and thereby stabilizing kinetochore-microtubule attachments, building tension, limiting Nde1-dependent dynein stripping of corona cargoes, and supporting biorientation [PMID:15854912, PMID:17600710, PMID:32207772]. CENP-F binds microtubules directly through two domains at opposite ends of the molecule, the C-terminal of which stimulates microtubule polymerization in vitro, and it can track growing and shrinking microtubule tips to transport cargo [PMID:16601978, PMID:23892111, PMID:28701340]. Its activity extends beyond mitosis: CENP-F regulates centrosomal microtubule nucleation via Hook2, transports mitochondria through a cell-cycle-dependent interaction with Miro, links the SNARE machinery (syntaxin 4/SNAP-25/VAMP2) to microtubule-based vesicular transport, and governs interphase microtubule dynamics underlying migration, focal adhesion turnover, and ciliogenesis [PMID:19793914, PMID:18827011, PMID:26259702, PMID:27146114]. CENP-F is farnesylated at its C-terminal CAAX box, a modification required for nuclear-envelope and kinetochore targeting and for post-mitotic degradation [PMID:10852915, PMID:12154071], and its abundance is controlled both by ubiquitin-proteasome turnover counteracted by the deubiquitinase USP4 and by periodic SETDB1-PC4-UPF1-mediated CENPF mRNA degradation [PMID:39922805, PMID:40016337]. Loss of CENP-F causes dilated cardiomyopathy in mice and a human ciliopathy (Strømme syndrome) [PMID:22563055, PMID:25564561].","teleology":[{"year":1993,"claim":"Established that CENP-F is a bona fide kinetochore-associated protein whose binding and release are coupled to mitotic progression rather than to microtubule presence.","evidence":"Affinity-purified antibody immunofluorescence and immunodepletion in HeLa cells","pmids":["7904902"],"confidence":"High","gaps":["Molecular determinant of kinetochore binding unknown","No information on cell-cycle regulation of abundance"]},{"year":1995,"claim":"Defined CENP-F's molecular architecture and cell-cycle dynamics, showing it is a coiled-coil nuclear matrix protein peaking at G2/M and degraded after mitosis.","evidence":"cDNA cloning, IF across the cell cycle, immunoelectron microscopy, and biochemical fractionation","pmids":["7542657"],"confidence":"High","gaps":["Function of predicted P-loop motif never validated","Mechanism of post-mitotic degradation not addressed"]},{"year":2002,"claim":"Showed CENP-F is farnesylated and that this lipid modification is required for nuclear-envelope/kinetochore targeting and post-mitotic turnover, defining a regulatory handle exploited by farnesyl transferase inhibitors.","evidence":"In vitro farnesyl transferase assays, metabolic labeling, FTI treatment, and CAAX mutagenesis with localization readouts","pmids":["10852915","12154071"],"confidence":"High","gaps":["How farnesylation mechanistically promotes membrane/kinetochore targeting unresolved","Mouse work later showed farnesylated C-terminus dispensable for development"]},{"year":2004,"claim":"Placed CENP-F in a hierarchical kinetochore assembly pathway, showing its recruitment depends on constitutive (CENP-I) and checkpoint (Bub1) components.","evidence":"RNAi depletion of CENP-I and Bub1 with IF localization readouts of CENP-F","pmids":["12640463","15020684"],"confidence":"High","gaps":["Direct versus indirect recruitment not distinguished at this stage","Binding interface not mapped"]},{"year":2006,"claim":"Demonstrated that CENP-F maintains kinetochore-microtubule attachment stability, sister tension, and checkpoint integrity, and is itself a direct microtubule-binding protein with polymerization-stimulating activity.","evidence":"RNAi with live-cell Mad1 imaging and inter-kinetochore measurements, plus in vitro MT binding/polymerization assays with purified domains","pmids":["16252009","16219694","16601978"],"confidence":"High","gaps":["Structural basis of MT binding not resolved","Relative contributions of two MT-binding domains unclear"]},{"year":2007,"claim":"Identified CENP-F as the recruitment hub linking the Ndel1/Nde1/Lis1/dynein motor pathway to kinetochores via direct interaction.","evidence":"Co-IP and reciprocal RNAi epistasis with localization readouts","pmids":["17600710"],"confidence":"High","gaps":["Binding interface for Nde1/Ndel1 not mapped at residue level here"]},{"year":2009,"claim":"Extended CENP-F function to the centrosome, showing it controls centrosomal (but not Golgi) microtubule nucleation through Hook2.","evidence":"Y2H and co-IP plus MT repolymerization assays in CENP-F(-/-) MEFs","pmids":["19793914"],"confidence":"High","gaps":["Mechanism by which CENP-F-Hook2 promotes nucleation/anchoring unresolved"]},{"year":2013,"claim":"Resolved the distinct microtubule-binding properties of CENP-F's two domains, showing the N-terminal domain binds with Ndc80-like affinity in a disordered geometry consistent with initial lateral attachment.","evidence":"Cosedimentation assays and electron microscopy of domain-microtubule complexes","pmids":["23892111"],"confidence":"High","gaps":["In vivo relevance of disordered binding geometry untested","Single lab"]},{"year":2018,"claim":"Defined the molecular specificity of CENP-F kinetochore recruitment, reconstituting a direct CENP-F coiled-coil/BUB1 kinase-domain interaction and separating Nup133 and BUB1 binding interfaces.","evidence":"Biochemical reconstitution and structure-guided mutagenesis with RNAi/localization readouts","pmids":["29748388","29632243"],"confidence":"High","gaps":["Whether BUB1 kinase activity is required for binding unclear","CENP-E redundancy in recruitment not fully quantified"]},{"year":2020,"claim":"Used separation-of-function mutants to assign discrete kinetochore activities, showing MT-binding domains stabilize attachments and transduce force while a distinct Nde1-binding domain limits dynein-mediated corona stripping.","evidence":"CRISPR-engineered mutants, live-cell imaging, quantitative attachment analysis, and co-IP","pmids":["32207772"],"confidence":"High","gaps":["How CENP-F-Nde1 antagonizes dynein mechanistically not fully resolved"]},{"year":2017,"claim":"Explained the spatial control of CENP-F's dual nuclear/cytoplasmic life, showing Cdk1 phosphorylation of its bipartite NLS weakens karyopherin-alpha binding to drive G2 nuclear export, and that CENP-F tracks dynamic microtubule tips to transport cargo.","evidence":"NLS phosphosite mutagenesis with karyopherin-alpha binding assays, plus in vitro tip-tracking reconstitution and live imaging","pmids":["28723232","28701340"],"confidence":"High","gaps":["Identity of export receptor downstream of NLS phospho-regulation not defined","How tip-tracking is mechanically achieved unresolved"]},{"year":2015,"claim":"Established CENP-F's non-mitotic transport role, showing a cell-cycle-dependent Miro interaction recruits it to mitochondria to drive peripheral mitochondrial spreading at cytokinesis.","evidence":"Co-IP, live imaging, and RNAi with quantitative mitochondrial distribution analysis","pmids":["26259702"],"confidence":"High","gaps":["Coupling between Miro recruitment and tip-tracking not directly demonstrated"]},{"year":2008,"claim":"Linked CENP-F to vesicular transport by showing it bridges the SNARE machinery to microtubules and supports GLUT4 trafficking.","evidence":"Y2H, co-IP of endogenous syntaxin 4/SNAP-25/VAMP2, RNAi, and GLUT4 trafficking assays","pmids":["18827011"],"confidence":"High","gaps":["Direct binding interface with syntaxin 4 not mapped","Generalizability beyond GLUT4 cargo untested"]},{"year":2016,"claim":"Demonstrated that CENP-F broadly governs interphase microtubule dynamics underlying migration, focal adhesion turnover, and ciliogenesis, expanding its role beyond mitosis.","evidence":"CENP-F(-/-) MEFs with live MT-dynamics imaging and functional assays","pmids":["27146114"],"confidence":"High","gaps":["Molecular mechanism connecting CENP-F to MT dynamics not pinpointed"]},{"year":2023,"claim":"Refined the conserved kinetochore module, showing BUB-1/HCP-1/2/CLS-2 (the BHC module) synergistically stabilize microtubules and promote pause, meaning CENP-F orthologs actively control MT dynamics rather than merely targeting CLASP.","evidence":"In vitro MT stabilization/pause assays plus in vivo structure-function in C. elegans (building on earlier CLASP-targeting work)","pmids":["36799894","15854912"],"confidence":"High","gaps":["Direct extrapolation of synergistic activity to human CENP-F kinetochores untested"]},{"year":2025,"claim":"Defined how CENP-F abundance is set, identifying USP4-mediated deubiquitination as a stabilizer, SETDB1-PC4-UPF1 as a periodic mRNA-degradation machine, and importin-beta/microtubule integrity as controllers of mitotic localization and timed degradation.","evidence":"Co-IP/ubiquitination assays, RNA-IP and mRNA stability assays, and proximity ligation with overexpression/MT-depolymerization experiments","pmids":["39922805","40016337","40596417"],"confidence":"Medium","gaps":["E3 ligase for CENP-F not identified in these findings","Importin-beta link rests on proximity ligation rather than classical co-IP"]},{"year":2012,"claim":"Provided in vivo disease relevance, showing cardiac-specific CENP-F deletion causes fully penetrant dilated cardiomyopathy with microtubule and intercalated-disc disruption.","evidence":"Cre-loxP conditional knockout in cardiomyocytes with histology, IF, and cardiac functional analysis","pmids":["22563055"],"confidence":"High","gaps":["Whether cardiomyopathy stems from mitotic versus interphase MT defects not resolved"]},{"year":2015,"claim":"Connected CENP-F to human ciliopathy, showing it localizes to mother-centriole subdistal appendages, co-IPs with IFT88, and that CENPF mutations cause truncated cilia (Strømme syndrome).","evidence":"Whole exome sequencing, co-IP with IFT88, IF co-localization, and patient tissue analysis","pmids":["25564561"],"confidence":"Medium","gaps":["Mechanism linking CENP-F to IFT-dependent ciliogenesis unresolved","Single lab"]},{"year":2024,"claim":"Revealed a nuclear transcriptional role, showing CENP-F co-regulates G2/M gene expression with FOXM1 by supporting chromatin accessibility and FOXM1-MBB complex formation in a cancer-specific manner.","evidence":"CRISPR loss-of-function with ATAC-seq, ChIP, and FOXM1-MBB co-IP","pmids":["38779933"],"confidence":"Medium","gaps":["How a kinetochore/MT protein acts in transcription mechanistically unclear","Single lab"]},{"year":null,"claim":"How CENP-F's many spatially distinct activities — kinetochore scaffolding, tip-tracking cargo transport, centrosomal nucleation, and transcriptional co-regulation — are coordinated by a single molecule, and which E3 ligase drives its post-mitotic destruction, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["E3 ubiquitin ligase for CENP-F not identified in the corpus","No integrated structural model of the full-length protein","Mechanistic basis of cancer-specific transcriptional role unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,14,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,11,13]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3,19]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[12,23]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10,14,16,27]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,9,18,20]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,15,16]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[12,23,27]}],"complexes":["kinetochore","Ndel1/Nde1/Lis1/dynein pathway","syntaxin 4/SNAP-25/VAMP2 SNARE complex","FOXM1-MBB complex"],"partners":["BUB1","CENP-E","NUP133","NDE1","NDEL1","HOOK2","MIRO","USP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49454","full_name":"Centromere protein F","aliases":["AH antigen","Kinetochore protein CENPF","Mitosin"],"length_aa":3114,"mass_kda":357.5,"function":"Required for kinetochore function and chromosome segregation in mitosis. Required for kinetochore localization of dynein, LIS1, NDE1 and NDEL1. Regulates recycling of the plasma membrane by acting as a link between recycling vesicles and the microtubule network though its association with STX4 and SNAP25. Acts as a potential inhibitor of pocket protein-mediated cellular processes during development by regulating the activity of RB proteins during cell division and proliferation. May play a regulatory or permissive role in the normal embryonic cardiomyocyte cell cycle and in promoting continued mitosis in transformed, abnormally dividing neonatal cardiomyocytes. Interaction with RB directs embryonic stem cells toward a cardiac lineage. Involved in the regulation of DNA synthesis and hence cell cycle progression, via its C-terminus. Has a potential role regulating skeletal myogenesis and in cell differentiation in embryogenesis. Involved in dendritic cell regulation of T-cell immunity against chlamydia","subcellular_location":"Cytoplasm, perinuclear region; Nucleus matrix; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/P49454/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CENPF","classification":"Not Classified","n_dependent_lines":178,"n_total_lines":1208,"dependency_fraction":0.14735099337748345},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"H1F0","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CENPF","total_profiled":1310},"omim":[{"mim_id":"616327","title":"CHROMOSOME ALIGNMENT-MAINTAINING PHOSPHOPROTEIN 1; CHAMP1","url":"https://www.omim.org/entry/616327"},{"mim_id":"609264","title":"NUCLEOPORIN, 37-KD; NUP37","url":"https://www.omim.org/entry/609264"},{"mim_id":"609263","title":"SEH1-LIKE PROTEIN; SEH1L","url":"https://www.omim.org/entry/609263"},{"mim_id":"608141","title":"NUCLEOPORIN, 43-KD; NUP43","url":"https://www.omim.org/entry/608141"},{"mim_id":"607617","title":"NUCLEOPORIN, 107-KD; NUP107","url":"https://www.omim.org/entry/607617"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":19.8},{"tissue":"lymphoid tissue","ntpm":23.7},{"tissue":"testis","ntpm":7.3}],"url":"https://www.proteinatlas.org/search/CENPF"},"hgnc":{"alias_symbol":["hcp-1"],"prev_symbol":[]},"alphafold":{"accession":"P49454","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49454","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CENPF","jax_strain_url":"https://www.jax.org/strain/search?query=CENPF"},"sequence":{"accession":"P49454","fasta_url":"https://rest.uniprot.org/uniprotkb/P49454.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49454/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49454"}},"corpus_meta":[{"pmid":"7542657","id":"PMC_7542657","title":"CENP-F is a protein of the nuclear matrix that assembles onto kinetochores at late G2 and is rapidly degraded after mitosis.","date":"1995","source":"The Journal of cell 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The predicted structure consists of two ~1,600-amino acid coiled-coil domains flanking a central flexible core, with a putative P-loop nucleotide binding site (ADIPTGKT) in the globular C-terminus.\",\n      \"method\": \"cDNA cloning, immunofluorescence across cell cycle stages, immunoelectron microscopy, nuclease digestion, cell fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IF, IEM, biochemical fractionation), foundational characterization replicated in subsequent studies\",\n      \"pmids\": [\"7542657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CENP-F associates with kinetochores independent of tubulin, and its dissociation from kinetochores is dependent on events connected with the onset of anaphase. CENP-F localizes to the outer surface of the outer kinetochore plate.\",\n      \"method\": \"Immunofluorescence with affinity-purified antibodies, immune depletion experiments, indirect immunofluorescence on HeLa cells\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cytological and biochemical experiments, replicated by subsequent studies\",\n      \"pmids\": [\"7904902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CENP-F is farnesylated in tumor cells (DLD-1): peptides from the COOH-terminal CAAX box of CENP-F are substrates for farnesyl transferase but not geranylgeranyl transferase-I, and prenylation is completely inhibited by the farnesyl transferase inhibitor SCH 66336. Preventing farnesylation does not affect kinetochore localization of CENP-F but alters the association between CENP-E and microtubules.\",\n      \"method\": \"In vitro farnesyl transferase substrate assay, metabolic labeling in DLD-1 cells, immunohistochemistry with FTI treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic substrate assay plus cell-based validation, independently confirmed by multiple subsequent studies\",\n      \"pmids\": [\"10852915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Farnesylation of CENP-F is required for its localization to the nuclear envelope at G2/M and to kinetochores in prometaphase, for timely G2/M progression, and for CENP-F degradation after mitosis. Ectopic expression of the kinetochore targeting domain delays G2/M progression in a CAAX motif-dependent manner.\",\n      \"method\": \"Ectopic expression of CENP-F kinetochore targeting domain with CAAX mutation, farnesyl transferase inhibitor treatment, immunofluorescence localization, cell cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CAAX mutagenesis combined with FTI treatment and localization readouts, replicated in multiple subsequent studies\",\n      \"pmids\": [\"12154071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CENP-F directly interacts with CENP-E (via yeast two-hybrid using CENP-E kinetochore binding domain as bait) and assembles onto kinetochores sequentially after CENP-E. CENP-F, BubR1, and CENP-E define discrete steps along the kinetochore assembly pathway.\",\n      \"method\": \"Yeast two-hybrid screen using CENP-E kinetochore binding domain, immunofluorescence co-localization, sequential kinetochore assembly analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid interaction, supported by co-localization data and assembly-order observations across multiple labs\",\n      \"pmids\": [\"9763420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bub1 is required for kinetochore localization of CENP-F (as well as BubR1, Cenp-E, and Mad2) in human somatic cells; RNAi-mediated depletion of Bub1 prevents subsequent CENP-F kinetochore assembly.\",\n      \"method\": \"RNA interference (RNAi) depletion of Bub1 in human cells, immunofluorescence to assess kinetochore localization of CENP-F and other checkpoint proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi epistasis with direct localization readout, replicated independently\",\n      \"pmids\": [\"15020684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CENP-I (a constitutive kinetochore protein) is required for kinetochore localization of CENP-F and checkpoint proteins MAD1 and MAD2; depletion of CENP-I causes G2 delay and prevents mitotic arrest.\",\n      \"method\": \"RNAi depletion of CENP-I, immunofluorescence for CENP-F and checkpoint protein localization, cell cycle analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi epistasis with direct localization phenotype, published in high-impact journal with rigorous controls\",\n      \"pmids\": [\"12640463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In C. elegans, HCP-1/2 (CENP-F orthologs) physically associate with CLASP (CLS-2) and are required for its kinetochore localization; CLASP depletion does not prevent HCP-1/2 targeting. The key role of HCP-1/2 is to target CLASP to kinetochores to promote microtubule polymerization at kinetochore-bound microtubules and ensure sister-chromatid biorientation.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, RNAi depletion, immunofluorescence localization in C. elegans embryos, genetic epistasis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical purification plus epistatic RNAi with direct localization readout, replicated with multiple orthogonal methods\",\n      \"pmids\": [\"15854912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CENP-F depletion by RNAi causes reduced stability of kinetochore microtubules, reduced tension between sister kinetochores of aligned chromosomes, merotelic associations, and continuous or intermittent Mad1 recruitment ('twinkling') indicating cycles of spindle checkpoint reactivation and silencing. A subset of CENP-F-depleted cells show complete failure of kinetochore assembly.\",\n      \"method\": \"RNAi depletion, live-cell imaging with YFP-Mad1, inter-kinetochore distance measurements, immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging combined with RNAi and quantitative functional readouts\",\n      \"pmids\": [\"16252009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CENP-F RNAi causes failure of metaphase chromosome alignment, anaphase segregation, and cytokinesis; kinetochores can still attach microtubules but oscillatory movements and inter-kinetochore distances are severely reduced. CENP-F depletion also causes premature loss of centromeric chromatid cohesion. The prolonged mitosis induced by CENP-F RNAi is dependent on the spindle checkpoint kinase BubR1.\",\n      \"method\": \"RNAi, immunofluorescence, live-cell imaging, epistasis with BubR1 RNAi\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts with RNAi, clear epistasis established\",\n      \"pmids\": [\"16219694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CENP-F is a novel microtubule-binding protein with two microtubule-binding domains at opposite ends of the molecule; the C-terminal microtubule-binding domain stimulates microtubule polymerization in vitro. CENP-F depletion causes cells to exit mitosis despite defective kinetochore attachments and reduces kinetochore levels of Mad1, Mad2, hBUBR1, hBUB1, and hMps1.\",\n      \"method\": \"In vitro microtubule binding and polymerization assays with purified CENP-F domains, RNAi depletion, immunofluorescence quantification of checkpoint proteins\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro microtubule binding and polymerization reconstitution assay plus cell-based RNAi phenotypic analysis\",\n      \"pmids\": [\"16601978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CENP-F directly interacts with Ndel1 and Nde1 (NudE-related proteins), and is required for kinetochore localization of Ndel1, Nde1, and Lis1. Nde1 (but not Ndel1) is required for kinetochore localization of dynein. CENP-F thus links the Ndel1/Nde1/Lis1/dynein pathway to kinetochores.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion of CENP-F, Nde1, and Ndel1, immunofluorescence for localization, chromosome alignment assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus epistatic RNAi with direct localization readouts, clear pathway hierarchy established\",\n      \"pmids\": [\"17600710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CENP-F localizes to the centrosome and interacts with Hook2 (a centrosomal linker protein) via yeast two-hybrid and co-immunoprecipitation. Loss of CENP-F in CENP-F(-/-) cells eliminates centrosome-specific microtubule repolymerization after nocodazole treatment, but MT repolymerization from the Golgi is unaffected, indicating CENP-F regulates centrosomal MT nucleation and anchoring.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, CENP-F(-/-) MEFs, microtubule repolymerization assay after nocodazole washout, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by co-IP, genetic KO model with specific functional assay\",\n      \"pmids\": [\"19793914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Murine CENP-F interacts with syntaxin 4 (a SNARE complex component) via yeast two-hybrid and co-immunoprecipitation. Endogenous CENP-F forms a complex with syntaxin 4, SNAP-25, and VAMP2. CENP-F depletion disrupts GLUT4 trafficking, and dominant-negative CENP-F inhibits cell coupling, demonstrating a role in vesicular transport through linking the SNARE system to the microtubule network.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal colocalization, RNAi depletion, dominant-negative expression, GLUT4 trafficking assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by co-IP with endogenous proteins, loss-of-function with specific trafficking readout\",\n      \"pmids\": [\"18827011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal microtubule-binding domain of CENP-F binds microtubules with affinity similar to the Ndc80 complex, while the C-terminal domain shows much lower affinity. EM analysis reveals both domains engage the microtubule surface in a disordered manner with no favored binding geometry, suggesting they may facilitate initial lateral attachments.\",\n      \"method\": \"Biochemical microtubule binding assays (cosedimentation), electron microscopy of domain-microtubule complexes\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical reconstitution with structural (EM) validation, single lab\",\n      \"pmids\": [\"23892111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CENP-F interacts directly with the mitochondrial protein Miro in a cell cycle-dependent manner. Cenp-F is recruited to mitochondria by Miro at the time of cytokinesis and associates with microtubule growing tips. Loss of CENP-F or Miro decreases spreading of the mitochondrial network and causes cytokinesis-specific defects in mitochondrial transport toward the cell periphery.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, RNAi depletion of CENP-F and Miro, quantitative mitochondrial distribution analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct co-IP interaction confirmed, live imaging with loss-of-function showing specific mitochondrial transport defect\",\n      \"pmids\": [\"26259702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CENP-F tracks growing microtubule ends in living cells. In vitro reconstitution demonstrates that microtubule tips can transport CENP-F-coated artificial cargoes over micrometer-long distances during both growing and shrinking phases, establishing CENP-F as a tip-tracking transporter for mitochondria and other cargoes.\",\n      \"method\": \"Live-cell imaging of CENP-F tracking, in vitro reconstitution assay with CENP-F-coated beads and dynamic microtubules\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of tip-tracking plus live-cell imaging confirmation\",\n      \"pmids\": [\"28701340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CENP-F contains a bipartite classical nuclear localization signal (cNLS) with three Cdk1 phosphorylation sites. Phosphomimetic mutations at these sites strongly reduce the interaction between the CENP-F cNLS and karyopherin α (importin α), and diminish nuclear localization. Cdk1-mediated phosphorylation of the cNLS in G2 phase thus regulates CENP-F nuclear export, enabling its cytoplasmic functions.\",\n      \"method\": \"Identification and mutagenesis of cNLS phosphorylation sites, binding assay between cNLS peptides and karyopherin α, cell localization assay with phosphomimetic mutants\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding assay with mutagenesis plus cellular localization validation, single lab\",\n      \"pmids\": [\"28723232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CENP-F directly and specifically interacts with BUB1 (but not BUBR1), whereas CENP-E directly interacts with BUBR1 (but not BUB1). The CENP-F/BUB1 interaction requires a dimeric coiled-coil in CENP-F and the kinase domain of BUB1, established by biochemical reconstitution. BUB1 is stringently required for CENP-F kinetochore localization while BUBR1 is dispensable for CENP-E localization. Both are recruited to kinetochores independently of the RZZ complex.\",\n      \"method\": \"Biochemical reconstitution of direct interactions, mutagenesis of binding determinants, RNAi depletion of BUB1/BUBR1 with immunofluorescence localization readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with mutagenesis plus cell-based epistasis, clear specificity established\",\n      \"pmids\": [\"29748388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Cenp-F C-terminal region contains separate binding sites for Nup133 and Bub1. Nup133 interacts with a conserved helix within its β-propeller and a short leucine zipper-containing dimeric segment of Cenp-F, mediating localization to nuclear pores in prophase. A point mutation in an adjacent leucine zipper impairs Bub1 interaction and kinetochore targeting of the Cenp-F KT-core domain without affecting Nup133 binding. Cenp-E redundantly contributes with Bub1 to Cenp-F kinetochore recruitment.\",\n      \"method\": \"In silico structural modeling, yeast two-hybrid assays, structure-guided mutagenesis, immunofluorescence localization of mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid with structure-guided mutagenesis separating two distinct binding interfaces, confirmed by cellular localization\",\n      \"pmids\": [\"29632243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CENP-F contains two microtubule-binding domains that make distinct contributions: they stabilize kinetochore-microtubule attachments and contribute to force transduction but are dispensable for chromosome congression. A specialized domain interacts directly with Nde1 to limit dynein-mediated stripping of corona cargoes; this antagonistic activity is crucial for maintaining corona composition and ensuring efficient kinetochore biorientation.\",\n      \"method\": \"CRISPR gene editing, engineered separation-of-function mutants, live-cell imaging, quantitative kinetochore attachment analysis, co-immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR separation-of-function mutants with multiple orthogonal functional readouts and direct interaction evidence\",\n      \"pmids\": [\"32207772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rab5 (a small GTPase that regulates vesicular trafficking) forms a complex with a subset of CENP-F in mitotic cells and regulates the kinetics of CENP-F release from the nuclear envelope and its accumulation on kinetochores. Simultaneous depletion of both Rab5 and CENP-F recapitulates the individual depletion mitotic defects, indicating epistatic roles for these two proteins in chromosome congression.\",\n      \"method\": \"RNAi, co-immunoprecipitation of Rab5 and CENP-F from mitotic cells, immunofluorescence, double-depletion epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus epistatic RNAi, single lab, mechanistic details of the complex not fully resolved\",\n      \"pmids\": [\"21987812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Both the amino and carboxy termini of KSHV LANA bind to CENP-F, and LANA co-localizes with CENP-F at centromeric regions. LANA also associates with Bub1, which forms a complex with CENP-F. FISH demonstrates co-localization of Bub1, LANA, and KSHV episome tethered to host chromosome. Knockdown of Bub1 (but not CENP-F) dramatically reduces KSHV genome copy number, suggesting the LANA-CENP-F/Bub1 interaction contributes to viral genome persistence.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, FISH, shRNA knockdown of Bub1 and CENP-F with genome copy number quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction with functional validation by knockdown, but CENP-F knockdown showed no dramatic effect on genome maintenance\",\n      \"pmids\": [\"20660191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CENP-F co-localizes with Ninein at the subdistal appendages of the mother centriole and co-immunoprecipitates with IFT88 from mitotic and serum-starved HEK293 cells. Mutations in CENPF cause ciliopathy with truncated cilia and failure of IFT88 to co-localize with CENP-F along ciliary axonemes, establishing a role for CENP-F in ciliogenesis.\",\n      \"method\": \"Whole exome sequencing, co-immunoprecipitation of CENP-F with IFT88, immunofluorescence co-localization in renal epithelial cells, analysis of patient tissue with CENPF mutations\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction, patient tissue showing loss-of-function ciliary phenotype, single lab\",\n      \"pmids\": [\"25564561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNAi depletion of CENP-F markedly downregulates methylation of histone H3 at K4 and K9, and decreases association of HP1α with mitotic chromosomes, revealing a role for CENP-F in regulating epigenetic histone H3 modifications.\",\n      \"method\": \"RNAi, immunofluorescence for H3K4me and H3K9me, HP1α localization analysis\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RNAi + IF), no direct biochemical mechanism established for how CENP-F influences methyltransferase activity\",\n      \"pmids\": [\"20213041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of C-terminal CENP-F deletion mutants induces interphase chromatin condensation into aggregates. CENP-F associates with DNA-dependent protein kinase (DNA-PK) by co-immunoprecipitation, and the DNA-PK association activity of CENP-F mutants correlates with their ability to induce chromatin aggregation.\",\n      \"method\": \"Overexpression of truncation mutants, co-immunoprecipitation with DNA-PK, in situ hybridization with chromosome painting probes\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, overexpression artifacts possible, single lab with no functional validation beyond correlation\",\n      \"pmids\": [\"20978035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cardiac-specific deletion of CENP-F in murine cardiomyocytes causes decreased cell division, blunted trabeculation, disruption of intercalated discs, loss of microtubule integrity at the costamere, and 100% development of progressive dilated cardiomyopathy with heart block and scarring, establishing a direct genetic link between CENP-F loss and cardiomyopathy.\",\n      \"method\": \"Cre-loxP conditional knockout in murine cardiomyocytes, histology, immunofluorescence for microtubule and intercalated disc components, cardiac functional analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional genetic KO with defined cellular and organ-level phenotypes, multiple readouts\",\n      \"pmids\": [\"22563055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CENP-F(-/-) mouse embryonic fibroblasts show severely diminished microtubule dynamics during interphase, which underlies defects in cell migration, focal adhesion dynamics, and primary cilia formation, demonstrating CENP-F regulates MT dynamics and heterogeneous cellular functions outside of cell division.\",\n      \"method\": \"Genetic deletion model (CENP-F(-/-) MEFs), live-cell microtubule dynamics imaging, cell migration assays, immunofluorescence for focal adhesions and cilia\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal functional readouts in interphase cells\",\n      \"pmids\": [\"27146114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Miro-deficient CENP-F point mutant (deficient in Miro binding) causes a defect in mitochondrial spreading in cultured cells similar to Miro depletion. Mice with this mutation or truncations lacking the farnesylated C-terminus develop normally, indicating the Miro-dependent mitochondrial pool of CENP-F and its farnesylated C-terminus are dispensable for normal murine development.\",\n      \"method\": \"CRISPR/Cas9-engineered CENP-F point mutation abolishing Miro binding, mouse knock-in models, live-cell mitochondrial distribution imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR separation-of-function mutation with in vivo mouse model and specific functional readout\",\n      \"pmids\": [\"30856164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Importin beta generates proximity ligation products with CENP-F during mitosis. Importin beta overexpression alters CENP-F mitotic localization (promoting accumulation at spindle poles and decreasing kinetochore association) and causes persistence of CENP-F into late mitosis when it normally disappears, in a process requiring microtubule integrity. This implicates importin beta in the spatial and temporal control of CENP-F during mitosis and reveals a protective role of microtubules against premature CENP-F ubiquitination.\",\n      \"method\": \"Proximity ligation assay, importin beta overexpression, immunofluorescence, microtubule depolymerization experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proximity ligation (not classical co-IP) plus functional overexpression with localization readout, single lab\",\n      \"pmids\": [\"40596417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP4 interacts with and stabilizes CENP-F via deubiquitination. CENP-F undergoes degradation via the ubiquitination-proteasome pathway in colorectal cancer cells. Clinical samples confirm that USP4 expression positively correlates with CENP-F protein but not mRNA levels, establishing USP4 as a deubiquitinase that controls CENP-F stability.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, Western blot for protein levels, clinical sample correlation analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction, mechanistic link to ubiquitin-proteasome pathway validated in cells and clinical samples, single lab\",\n      \"pmids\": [\"39922805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SETDB1-PC4-UPF1 constitutes a post-transcriptional machinery that controls periodic degradation of CENPF mRNA. In early G2, newly synthesized CENPF mRNAs bind to PC4; SETDB1 then dimethylates PC4 at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of CENPF mRNAs.\",\n      \"method\": \"RNA immunoprecipitation, protein interaction assays, methylation assays, mRNA stability assays, cell cycle synchronization\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical mechanism of mRNA regulation established with multiple components, single lab\",\n      \"pmids\": [\"40016337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CENPF mRNA is subject to N6-methyladenosine (m6A) modification mediated by METTL3. This modification is recognized by HNRNPA2B1, which promotes CENPF mRNA stability. CENPF binds FAK and promotes its cytoplasmic localization; the metastatic function of CENPF is dependent on the MAPK signaling pathway.\",\n      \"method\": \"MeRIP-seq, RNA immunoprecipitation-qPCR, RNA pulldown, co-immunoprecipitation, mass spectrometry, immunofluorescence, gain/loss-of-function experiments\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods for m6A and HNRNPA2B1 interaction; CENPF-FAK co-IP established, single lab\",\n      \"pmids\": [\"37256823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CENP-F functions with FOXM1 to co-regulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in altered chromatin accessibility at G2/M genes and reduced FOXM1-MBB complex formation. This FOXM1-CENP-F transcriptional co-regulation is cancer-specific and involves CENP-F acting as an outer kinetochore component that also has a nuclear transcriptional role.\",\n      \"method\": \"CRISPR loss-of-function, ATAC-seq (chromatin accessibility), ChIP, co-immunoprecipitation for FOXM1-MBB complex, chromosome segregation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with chromatin accessibility and protein complex readouts, single lab with multiple methods\",\n      \"pmids\": [\"38779933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DNA damage-induced G2 arrest in HeLa cells (TP53-independent) occurs in early G2, before redistribution of CENP-F to the nuclear envelope and kinetochores and before chromosome condensation commences, using CENP-F localization as a precise cell cycle marker to define the arrest point.\",\n      \"method\": \"DNA damage treatment, immunofluorescence for CENP-F localization as a G2 stage marker, cell cycle analysis\",\n      \"journal\": \"Radiation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CENP-F used as stage-specific marker to define G2 arrest point; establishes CENP-F nuclear envelope/kinetochore translocation as a late-G2 landmark\",\n      \"pmids\": [\"12710871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, BUB-1, HCP-1/2 (CENP-F orthologs), and CLS-2 (CLASP) form a BHC kinetochore module that synergistically stabilizes microtubules and promotes microtubule pause. BUB-1 and HCP-1/2 do not only act as targeting factors for CLS-2 but also actively participate in controlling kinetochore-microtubule dynamics to promote meiotic spindle formation and accurate chromosome segregation.\",\n      \"method\": \"In vivo structure-function analysis with RNAi/mutations, in vitro microtubule stabilization and pause assays, live imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro microtubule assays combined with in vivo structure-function analysis showing synergistic activity, multiple orthogonal methods\",\n      \"pmids\": [\"36799894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CENPF targets Chk1-mediated G2/M phase arrest and binds to Rb to compete with E2F1 in triple-negative breast cancer cells; this competition at the Rb-E2F1 axis modulates the DNA damage response.\",\n      \"method\": \"Co-immunoprecipitation of CENPF with Rb, ChIP, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP for CENPF-Rb interaction, no reconstitution, single lab\",\n      \"pmids\": [\"36720923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CENPF interacts with PLA2G4A by co-immunoprecipitation and molecular docking. Silencing CENPF reduces mTORC1 signaling and EMT in glioma cells; the CENPF-PLA2G4A interaction promotes downstream oncogenic signaling. Combined silencing of CENPF and a PLA2G4A inhibitor shows synergistic anti-glioma effects.\",\n      \"method\": \"Molecular docking, co-immunoprecipitation, siRNA knockdown, Western blot for mTORC1 pathway, cell proliferation and invasion assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP confirmed interaction, but downstream mechanistic details rely largely on pathway inhibitor experiments, single lab\",\n      \"pmids\": [\"40025532\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CENP-F is a large (~367 kDa) farnesylated nuclear matrix protein that accumulates during S/G2, undergoes Cdk1-dependent nuclear export in G2 via phosphorylation of its bipartite NLS (weakening karyopherin α binding), localizes to the nuclear envelope (via Nup133 interaction) and then to kinetochores (via direct interaction with BUB1) from late G2 through anaphase, where it recruits the Ndel1/Nde1/Lis1/dynein pathway and CLASP to kinetochores, stabilizes kinetochore-microtubule attachments through two microtubule-binding domains, limits dynein-mediated corona stripping via Nde1, and is degraded after mitosis in a farnesylation- and microtubule/importin-beta-dependent manner; outside of mitosis, CENP-F also tracks dynamic microtubule tips to transport mitochondria (via Miro interaction), regulates centrosomal microtubule nucleation (via Hook2 interaction), participates in vesicular transport (via syntaxin 4/SNARE association), co-regulates G2/M transcription with FOXM1, and loss-of-function causes cardiomyopathy, ciliopathy (Strømme syndrome), and early embryonic lethality.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CENP-F is a large, cell-cycle-regulated nuclear matrix protein that functions as a multivalent microtubule-associated scaffold, accumulating during S/G2 and peaking at G2/M before being rapidly degraded after mitosis [#0]. Its mitotic role centers on the outer kinetochore: it loads onto kinetochores from late G2 through early anaphase downstream of constitutive and checkpoint components, requiring CENP-I and BUB1, with which it forms a direct, biochemically reconstituted complex via a CENP-F coiled-coil and the BUB1 kinase domain [#1, #5, #6, #18]. A separate C-terminal interface engages the nucleoporin Nup133 to drive nuclear-envelope/pore localization in prophase, while the adjacent BUB1-binding element targets the kinetochore-core domain [#19]. At kinetochores CENP-F serves as a recruitment hub, linking the Ndel1/Nde1/Lis1/dynein pathway and CLASP to the kinetochore and thereby stabilizing kinetochore-microtubule attachments, building tension, limiting Nde1-dependent dynein stripping of corona cargoes, and supporting biorientation [#7, #11, #20]. CENP-F binds microtubules directly through two domains at opposite ends of the molecule, the C-terminal of which stimulates microtubule polymerization in vitro, and it can track growing and shrinking microtubule tips to transport cargo [#10, #14, #16]. Its activity extends beyond mitosis: CENP-F regulates centrosomal microtubule nucleation via Hook2, transports mitochondria through a cell-cycle-dependent interaction with Miro, links the SNARE machinery (syntaxin 4/SNAP-25/VAMP2) to microtubule-based vesicular transport, and governs interphase microtubule dynamics underlying migration, focal adhesion turnover, and ciliogenesis [#12, #13, #15, #27]. CENP-F is farnesylated at its C-terminal CAAX box, a modification required for nuclear-envelope and kinetochore targeting and for post-mitotic degradation [#2, #3], and its abundance is controlled both by ubiquitin-proteasome turnover counteracted by the deubiquitinase USP4 and by periodic SETDB1-PC4-UPF1-mediated CENPF mRNA degradation [#30, #31]. Loss of CENP-F causes dilated cardiomyopathy in mice and a human ciliopathy (Strømme syndrome) [#26, #23].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that CENP-F is a bona fide kinetochore-associated protein whose binding and release are coupled to mitotic progression rather than to microtubule presence.\",\n      \"evidence\": \"Affinity-purified antibody immunofluorescence and immunodepletion in HeLa cells\",\n      \"pmids\": [\"7904902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinant of kinetochore binding unknown\", \"No information on cell-cycle regulation of abundance\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined CENP-F's molecular architecture and cell-cycle dynamics, showing it is a coiled-coil nuclear matrix protein peaking at G2/M and degraded after mitosis.\",\n      \"evidence\": \"cDNA cloning, IF across the cell cycle, immunoelectron microscopy, and biochemical fractionation\",\n      \"pmids\": [\"7542657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of predicted P-loop motif never validated\", \"Mechanism of post-mitotic degradation not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed CENP-F is farnesylated and that this lipid modification is required for nuclear-envelope/kinetochore targeting and post-mitotic turnover, defining a regulatory handle exploited by farnesyl transferase inhibitors.\",\n      \"evidence\": \"In vitro farnesyl transferase assays, metabolic labeling, FTI treatment, and CAAX mutagenesis with localization readouts\",\n      \"pmids\": [\"10852915\", \"12154071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How farnesylation mechanistically promotes membrane/kinetochore targeting unresolved\", \"Mouse work later showed farnesylated C-terminus dispensable for development\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed CENP-F in a hierarchical kinetochore assembly pathway, showing its recruitment depends on constitutive (CENP-I) and checkpoint (Bub1) components.\",\n      \"evidence\": \"RNAi depletion of CENP-I and Bub1 with IF localization readouts of CENP-F\",\n      \"pmids\": [\"12640463\", \"15020684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect recruitment not distinguished at this stage\", \"Binding interface not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that CENP-F maintains kinetochore-microtubule attachment stability, sister tension, and checkpoint integrity, and is itself a direct microtubule-binding protein with polymerization-stimulating activity.\",\n      \"evidence\": \"RNAi with live-cell Mad1 imaging and inter-kinetochore measurements, plus in vitro MT binding/polymerization assays with purified domains\",\n      \"pmids\": [\"16252009\", \"16219694\", \"16601978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MT binding not resolved\", \"Relative contributions of two MT-binding domains unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified CENP-F as the recruitment hub linking the Ndel1/Nde1/Lis1/dynein motor pathway to kinetochores via direct interaction.\",\n      \"evidence\": \"Co-IP and reciprocal RNAi epistasis with localization readouts\",\n      \"pmids\": [\"17600710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface for Nde1/Ndel1 not mapped at residue level here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended CENP-F function to the centrosome, showing it controls centrosomal (but not Golgi) microtubule nucleation through Hook2.\",\n      \"evidence\": \"Y2H and co-IP plus MT repolymerization assays in CENP-F(-/-) MEFs\",\n      \"pmids\": [\"19793914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CENP-F-Hook2 promotes nucleation/anchoring unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the distinct microtubule-binding properties of CENP-F's two domains, showing the N-terminal domain binds with Ndc80-like affinity in a disordered geometry consistent with initial lateral attachment.\",\n      \"evidence\": \"Cosedimentation assays and electron microscopy of domain-microtubule complexes\",\n      \"pmids\": [\"23892111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of disordered binding geometry untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the molecular specificity of CENP-F kinetochore recruitment, reconstituting a direct CENP-F coiled-coil/BUB1 kinase-domain interaction and separating Nup133 and BUB1 binding interfaces.\",\n      \"evidence\": \"Biochemical reconstitution and structure-guided mutagenesis with RNAi/localization readouts\",\n      \"pmids\": [\"29748388\", \"29632243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BUB1 kinase activity is required for binding unclear\", \"CENP-E redundancy in recruitment not fully quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Used separation-of-function mutants to assign discrete kinetochore activities, showing MT-binding domains stabilize attachments and transduce force while a distinct Nde1-binding domain limits dynein-mediated corona stripping.\",\n      \"evidence\": \"CRISPR-engineered mutants, live-cell imaging, quantitative attachment analysis, and co-IP\",\n      \"pmids\": [\"32207772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CENP-F-Nde1 antagonizes dynein mechanistically not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Explained the spatial control of CENP-F's dual nuclear/cytoplasmic life, showing Cdk1 phosphorylation of its bipartite NLS weakens karyopherin-alpha binding to drive G2 nuclear export, and that CENP-F tracks dynamic microtubule tips to transport cargo.\",\n      \"evidence\": \"NLS phosphosite mutagenesis with karyopherin-alpha binding assays, plus in vitro tip-tracking reconstitution and live imaging\",\n      \"pmids\": [\"28723232\", \"28701340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of export receptor downstream of NLS phospho-regulation not defined\", \"How tip-tracking is mechanically achieved unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established CENP-F's non-mitotic transport role, showing a cell-cycle-dependent Miro interaction recruits it to mitochondria to drive peripheral mitochondrial spreading at cytokinesis.\",\n      \"evidence\": \"Co-IP, live imaging, and RNAi with quantitative mitochondrial distribution analysis\",\n      \"pmids\": [\"26259702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between Miro recruitment and tip-tracking not directly demonstrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked CENP-F to vesicular transport by showing it bridges the SNARE machinery to microtubules and supports GLUT4 trafficking.\",\n      \"evidence\": \"Y2H, co-IP of endogenous syntaxin 4/SNAP-25/VAMP2, RNAi, and GLUT4 trafficking assays\",\n      \"pmids\": [\"18827011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with syntaxin 4 not mapped\", \"Generalizability beyond GLUT4 cargo untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that CENP-F broadly governs interphase microtubule dynamics underlying migration, focal adhesion turnover, and ciliogenesis, expanding its role beyond mitosis.\",\n      \"evidence\": \"CENP-F(-/-) MEFs with live MT-dynamics imaging and functional assays\",\n      \"pmids\": [\"27146114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting CENP-F to MT dynamics not pinpointed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the conserved kinetochore module, showing BUB-1/HCP-1/2/CLS-2 (the BHC module) synergistically stabilize microtubules and promote pause, meaning CENP-F orthologs actively control MT dynamics rather than merely targeting CLASP.\",\n      \"evidence\": \"In vitro MT stabilization/pause assays plus in vivo structure-function in C. elegans (building on earlier CLASP-targeting work)\",\n      \"pmids\": [\"36799894\", \"15854912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct extrapolation of synergistic activity to human CENP-F kinetochores untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined how CENP-F abundance is set, identifying USP4-mediated deubiquitination as a stabilizer, SETDB1-PC4-UPF1 as a periodic mRNA-degradation machine, and importin-beta/microtubule integrity as controllers of mitotic localization and timed degradation.\",\n      \"evidence\": \"Co-IP/ubiquitination assays, RNA-IP and mRNA stability assays, and proximity ligation with overexpression/MT-depolymerization experiments\",\n      \"pmids\": [\"39922805\", \"40016337\", \"40596417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for CENP-F not identified in these findings\", \"Importin-beta link rests on proximity ligation rather than classical co-IP\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided in vivo disease relevance, showing cardiac-specific CENP-F deletion causes fully penetrant dilated cardiomyopathy with microtubule and intercalated-disc disruption.\",\n      \"evidence\": \"Cre-loxP conditional knockout in cardiomyocytes with histology, IF, and cardiac functional analysis\",\n      \"pmids\": [\"22563055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cardiomyopathy stems from mitotic versus interphase MT defects not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected CENP-F to human ciliopathy, showing it localizes to mother-centriole subdistal appendages, co-IPs with IFT88, and that CENPF mutations cause truncated cilia (Strømme syndrome).\",\n      \"evidence\": \"Whole exome sequencing, co-IP with IFT88, IF co-localization, and patient tissue analysis\",\n      \"pmids\": [\"25564561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CENP-F to IFT-dependent ciliogenesis unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a nuclear transcriptional role, showing CENP-F co-regulates G2/M gene expression with FOXM1 by supporting chromatin accessibility and FOXM1-MBB complex formation in a cancer-specific manner.\",\n      \"evidence\": \"CRISPR loss-of-function with ATAC-seq, ChIP, and FOXM1-MBB co-IP\",\n      \"pmids\": [\"38779933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a kinetochore/MT protein acts in transcription mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CENP-F's many spatially distinct activities — kinetochore scaffolding, tip-tracking cargo transport, centrosomal nucleation, and transcriptional co-regulation — are coordinated by a single molecule, and which E3 ligase drives its post-mitotic destruction, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ubiquitin ligase for CENP-F not identified in the corpus\", \"No integrated structural model of the full-length protein\", \"Mechanistic basis of cancer-specific transcriptional role unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 14, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3, 19]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [12, 23]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10, 14, 16, 27]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 9, 18, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 15, 16]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [12, 23, 27]}\n    ],\n    \"complexes\": [\"kinetochore\", \"Ndel1/Nde1/Lis1/dynein pathway\", \"syntaxin 4/SNAP-25/VAMP2 SNARE complex\", \"FOXM1-MBB complex\"],\n    \"partners\": [\"BUB1\", \"CENP-E\", \"Nup133\", \"Nde1\", \"Ndel1\", \"Hook2\", \"Miro\", \"USP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}