{"gene":"AHCTF1","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2006,"finding":"ELYS co-purifies with the Nup107-160 complex in Xenopus interphase extracts, mitotic extracts, and human cell extracts (co-immunoprecipitation/mass spectrometry), and is required for nuclear pore assembly; RNAi depletion of ELYS in HeLa cells severely disrupts nuclear pores in the nuclear envelope and leads to cytokinesis defects, while lamin, Ran, and tubulin staining appear normal. At mitosis, ELYS targets to kinetochores.","method":"Co-immunoprecipitation, mass spectrometry, RNAi knockdown, immunofluorescence in HeLa cells and Xenopus extracts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with MS identification, RNAi phenotype replicated in multiple systems, multiple orthogonal methods","pmids":["17098863"],"is_preprint":false},{"year":2007,"finding":"MEL-28/ELYS (vertebrate homologue) is essential for post-mitotic NPC assembly; it interacts with the Nup107-160 complex and is required for recruitment of the Nup107-160 complex to chromatin, acting as a seeding point for NPC assembly, as demonstrated in in vitro nuclear envelope assembly assays.","method":"In vitro nuclear envelope assembly assay, immunodepletion, co-immunoprecipitation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assay with immunodepletion, replicated across labs","pmids":["17235358"],"is_preprint":false},{"year":2007,"finding":"ELYS contains an AT-hook domain that binds chromatin with high affinity; this domain competes with full-length ELYS for chromatin association thereby blocking NPC assembly. ELYS also physically associates with the Mcm2-7 replication-licensing proteins on chromatin, and ELYS chromatin loading is delayed when Mcm2-7 is prevented from loading.","method":"Xenopus egg extract cell-free system, proteomics, chromatin binding competition assay, co-immunoprecipitation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro chromatin binding, competition assay, physical association by co-IP, single lab with multiple orthogonal methods","pmids":["17825564"],"is_preprint":false},{"year":2008,"finding":"ELYS binds AT-rich chromatin via its AT-hook motif; point mutation of only two amino acids in the AT-hook blocks nuclear pore assembly. Chromatin-bound ELYS/Nup107-160 complex is required for recruitment of vesicles containing integral membrane pore proteins POM121 and NDC1 (but not gp210 vesicles). A direct interaction between the cytoplasmic domain of POM121 and the Nup107-160 complex was identified.","method":"Point mutagenesis, DNA-binding antibiotics competition assay, Xenopus in vitro nuclear assembly, co-immunoprecipitation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and pharmacological competition, single lab with multiple orthogonal methods","pmids":["18596237"],"is_preprint":false},{"year":2008,"finding":"In zebrafish elys mutants, Elys binds Mcm2-7 complexes from Xenopus egg extracts, and loss of Elys reduces chromatin binding of Mcm2 (but not Mcm3 or Mcm4) in the intestine, indicating a role for Elys in Mcm2-chromatin interactions and replication licensing.","method":"Zebrafish genetics (loss-of-function mutation), co-immunoprecipitation with Xenopus extracts, immunofluorescence/immunohistochemistry","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function plus biochemical pulldown, single lab with two orthogonal methods","pmids":["18974873"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of S. pombe Nup37 in complex with Nup120 (174-kDa subassembly) was determined; ELY5/ELYS (fission yeast ELYS ortholog) integrates into the Y-complex via Nup120/160 and binds near the Nup120-Nup37 interface, as shown by reconstitution assays and in vivo/in vitro biochemical data.","method":"X-ray crystallography (1.9 Å), reconstitution assays, in vivo and in vitro biochemical binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 1.9 Å with reconstitution and mutagenesis; fission yeast ortholog with conserved interactions","pmids":["22955883"],"is_preprint":false},{"year":2012,"finding":"ELYS/Mel28 is essential for recruiting the lamin B receptor (LBR) to the chromosomal noncore region during NE reassembly; this depends on Nup107 but not Pom121. ELYS/Mel28 biochemically interacts with LBR in a phosphorylation-dependent manner. ELYS/Mel28 also focuses A-type lamin-binding proteins (emerin, Lap2α, BAF) at the chromosomal core region.","method":"RNAi knockdown in HeLa cells, co-immunoprecipitation, immunofluorescence","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi knockdown with defined phenotype, co-IP showing phosphorylation-dependent interaction, single lab","pmids":["22555603"],"is_preprint":false},{"year":2013,"finding":"ELYS contains three domains: an N-terminal β-propeller domain (crystal structure resolved at 1.9 Å), a central α-helical domain, and a C-terminal disordered region. The disordered C-terminal region is responsible for chromatin interactions, while the β-propeller and α-helical domains synergistically mediate tethering to the NPC. Surface analysis of the β-propeller identifies regions required for NPC anchorage.","method":"X-ray crystallography (1.9 Å resolution), domain mapping/deletion analysis, biochemical binding assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with domain deletion functional analysis, single lab with two orthogonal methods","pmids":["23499022"],"is_preprint":false},{"year":2016,"finding":"ELYS depletion promotes LBR phosphorylation at CDK- and SRPK1/SRPK2-targeted residues; PP1 phosphatase normally counterbalances this phosphorylation; depletion of PP1 similarly mislocalizes LBR. These results define an ELYS-mediated phosphorylation network controlling LBR localization at the inner nuclear membrane.","method":"RNAi knockdown, phosphorylation analysis, kinase inhibitor experiments, PP1 depletion","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional RNAi knockdown with phosphorylation analysis and PP1 epistasis, single lab","pmids":["27802161"],"is_preprint":false},{"year":2016,"finding":"MEL-28/ELYS in C. elegans has distinct functional domains: an AT-hook domain required for function (but not localization) whose perturbation delays cell cycle progression in a DNA damage checkpoint-dependent manner; domains for nuclear envelope/kinetochore localization; chromatin binding; mitotic spindle matrix association; and chromosome segregation. A novel meiotic role was also identified.","method":"Systematic domain mutagenesis, RNAi, fluorescence microscopy, genetic epistasis in C. elegans and human cells","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain mutagenesis with multiple phenotypic readouts, single lab","pmids":["27341616"],"is_preprint":false},{"year":2017,"finding":"RNAs are required for proper ELYS recruitment to chromatin during nuclear envelope assembly in Xenopus egg extracts; RNA-depleted extracts show defective ELYS recruitment, impaired NPC assembly, failure in chromatin relaxation, and inability to import/concentrate S-phase kinases needed for DNA replication activation.","method":"Xenopus egg extract with RNA depletion, immunofluorescence, biochemical fractionation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with RNA depletion and rescue, single lab","pmids":["29242643"],"is_preprint":false},{"year":2019,"finding":"ELYS knockdown in human cells results in small nuclei, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import capacity; overexpression of importin α rescues nuclear size and lamin B2 import; ELYS overexpression increases nuclear size, NPC density, and nuclear import. ELYS thus controls nuclear size through regulation of NPC number and nuclear import capacity.","method":"High-throughput RNAi screen, importin α overexpression rescue, ELYS overexpression, nuclear import assay, immunofluorescence in mammalian cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with rescue experiment, single lab, multiple readouts","pmids":["31085625"],"is_preprint":false},{"year":2019,"finding":"The Arg-Arg-Lys (RRK) stretch of the C-terminal ELYS region is essential for nucleosome binding; cryo-EM structure and crosslinking mass spectrometry reveal that the ELYS C-terminal region directly binds the acidic patch of the nucleosome, providing a mechanism for how ELYS engages chromatin to initiate post-mitotic NPC assembly.","method":"Cryo-EM structure determination, crosslinking mass spectrometry, mutagenesis, binding assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with crosslinking MS and mutagenesis, single lab with multiple orthogonal methods","pmids":["31069272"],"is_preprint":false},{"year":2019,"finding":"AHCTF1/ELYS connects nucleoporins to the oncogenic MYC super-enhancer via β-catenin (WNT signaling effector), facilitating tethering of active MYC alleles to nuclear pores to increase transcript export rates, thereby reducing nuclear MYC mRNA degradation and increasing cytoplasmic MYC mRNA levels in colon cancer cells.","method":"ChIP, chromatin conformation/gene gating assays, RNA export measurements, AHCTF1 knockdown, β-catenin interaction assays","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional genomics methods, interaction assays and knockdown, single lab","pmids":["31784729"],"is_preprint":false},{"year":2020,"finding":"Drosophila ELYS (dElys) depletion leads to nuclear pore and nuclear lamina assembly defects; genetically, dElys depletion re-activates the Dorsal (NF-κB) pathway during late larval stages, causing ectopic expression of Dorsal target genes and up-regulation of pro-apoptotic genes reaper and hid leading to apoptosis. dElys contains a noncanonical AT-hook-like motif through which it strongly binds DNA.","method":"RNAi depletion, fluorescence and electron microscopy, genetic epistasis, quantitative PCR in Drosophila","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with genetic epistasis and defined pathway placement, single lab in Drosophila ortholog","pmids":["31941789"],"is_preprint":false},{"year":2022,"finding":"In C. elegans oocyte meiosis, MEL-28/ELYS (ortholog of human ELYS) acts in parallel with CENP-C to recruit outer kinetochore components to meiotic chromosomes. MEL-28 also independently links chromosomes to spindle microtubules together with the NDC-80 complex (part of the KMN network), and this function involves the Y-complex nucleoporins that associate with MEL-28. The PP1-docking function shared by MEL-28 and KNL-1 is not involved in microtubule linkage.","method":"Genetic epistasis, engineered separation-of-function mutants, RNAi, live imaging in C. elegans","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with engineered mutants and multiple combinations, single lab","pmids":["35609608"],"is_preprint":false},{"year":2024,"finding":"During mitosis, ELYS is phosphorylated at multiple sites including a predicted FFAT motif; this phosphorylation enables interaction with the MSP domain of membrane protein VAPB. In anaphase, ELYS and VAPB co-localize to the non-core region of the newly forming nuclear envelope. VAPB depletion results in prolonged mitosis, slow meta-to-anaphase progression, and chromosome segregation defects.","method":"Co-immunoprecipitation, recombinant protein binding assays, mass spectrometry, immunofluorescence, VAPB depletion","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with recombinant proteins, phospho-specific analysis, and knockdown phenotype, single lab","pmids":["38605278"],"is_preprint":false}],"current_model":"AHCTF1/ELYS is a large multidomain nucleoporin that initiates post-mitotic nuclear pore complex assembly by binding AT-rich chromatin (and nucleosome acidic patches) via its C-terminal disordered region/RRK stretch, then recruiting the Nup107-160/Y-complex scaffold, which in turn recruits POM121- and NDC1-containing membrane vesicles; it also interacts with Mcm2-7 replication licensing factors on chromatin, controls nuclear size by setting NPC density and nuclear import capacity, localizes to kinetochores during mitosis to ensure chromosome segregation, regulates inner nuclear membrane protein LBR localization through a phosphorylation network involving CDK/SRPK/PP1, interacts with VAPB via a phospho-FFAT motif during mitotic NE reassembly, and in cancer cells connects nucleoporins to WNT/β-catenin-driven oncogenic super-enhancers to facilitate MYC mRNA nuclear export."},"narrative":{"mechanistic_narrative":"AHCTF1 (ELYS/MEL-28) is the seeding nucleoporin that initiates post-mitotic nuclear pore complex (NPC) assembly by linking chromatin to the Nup107-160 (Y-complex) scaffold [PMID:17098863, PMID:17235358]. It is a multidomain protein comprising an N-terminal β-propeller, a central α-helical region that together mediate NPC anchorage, and a C-terminal disordered region responsible for chromatin engagement [PMID:23499022]; this C-terminal region binds AT-rich chromatin through an AT-hook motif and directly contacts the nucleosome acidic patch via its RRK stretch, with point mutations in the AT-hook abolishing NPC assembly [PMID:17825564, PMID:18596237, PMID:31069272]. Chromatin-bound ELYS recruits the Nup107-160 complex, which in turn brings in POM121- and NDC1-containing membrane vesicles to nucleate pores [PMID:17235358, PMID:18596237], integrating into the Y-complex at the Nup120/Nup37 interface [PMID:22955883]. Beyond pore seeding, ELYS sets nuclear size by controlling NPC density and nuclear import capacity, an activity rescuable by importin α [PMID:31085625], and it organizes inner nuclear membrane proteins during NE reassembly: it recruits the lamin B receptor (LBR) to the chromosomal non-core region through a CDK/SRPK/PP1 phosphorylation network and via a phospho-FFAT–dependent interaction with VAPB [PMID:22555603, PMID:27802161, PMID:38605278]. ELYS also associates with the Mcm2-7 replication-licensing machinery on chromatin, coupling pore assembly to replication competence [PMID:17825564, PMID:18974873], and localizes to kinetochores during mitosis where it ensures chromosome segregation [PMID:17098863, PMID:35609608]. In colon cancer cells, AHCTF1 tethers active MYC alleles to nuclear pores through β-catenin at WNT-driven super-enhancers, accelerating MYC mRNA export [PMID:31784729].","teleology":[{"year":2006,"claim":"Established that ELYS is a physical and functional partner of the Nup107-160 complex required for nuclear pore assembly, defining its central role at the nuclear envelope.","evidence":"Co-IP/MS and RNAi in HeLa cells and Xenopus extracts, with kinetochore targeting at mitosis","pmids":["17098863"],"confidence":"High","gaps":["Mechanism of chromatin engagement not yet defined","Direct vs scaffold-mediated kinetochore role unresolved"]},{"year":2007,"claim":"Showed ELYS acts upstream as the seeding point that recruits the Nup107-160 complex to chromatin, ordering the NPC assembly pathway.","evidence":"In vitro NE assembly assay with immunodepletion and Co-IP","pmids":["17235358"],"confidence":"High","gaps":["Chromatin determinant of recruitment unknown","Membrane vesicle step not yet placed"]},{"year":2007,"claim":"Identified the AT-hook chromatin-binding domain and linked ELYS to the Mcm2-7 replication-licensing machinery, connecting pore assembly to replication.","evidence":"Xenopus egg extract, chromatin binding competition, Co-IP","pmids":["17825564"],"confidence":"High","gaps":["Functional consequence of Mcm2-7 association for replication not established here","Whether interaction is direct unresolved"]},{"year":2008,"claim":"Demonstrated that AT-hook–mediated chromatin binding is essential for downstream recruitment of POM121/NDC1 membrane vesicles, completing the chromatin-to-membrane assembly chain.","evidence":"Point mutagenesis, DNA-binding antibiotic competition, Xenopus in vitro assembly, Co-IP","pmids":["18596237"],"confidence":"High","gaps":["gp210 vesicle recruitment pathway distinct and unaddressed","Structural basis of POM121-Y-complex contact unknown"]},{"year":2008,"claim":"Provided in vivo genetic support that Elys promotes Mcm2-chromatin loading, implicating it in replication licensing in an intact organism.","evidence":"Zebrafish loss-of-function mutants, Co-IP with Xenopus extracts, immunohistochemistry","pmids":["18974873"],"confidence":"Medium","gaps":["Selectivity for Mcm2 over Mcm3/4 mechanistically unexplained","Cross-species pulldown leaves directness uncertain"]},{"year":2012,"claim":"Resolved how ELYS integrates structurally into the Y-complex via the Nup120/Nup37 interface.","evidence":"X-ray crystallography (1.9 Å) of Nup37–Nup120 with reconstitution and binding assays in fission yeast ortholog","pmids":["22955883"],"confidence":"High","gaps":["Human complex geometry inferred from ortholog","Stoichiometry within assembled NPC not addressed"]},{"year":2012,"claim":"Extended ELYS function to inner nuclear membrane organization by showing it recruits LBR and focuses A-type lamin-binding proteins during NE reassembly.","evidence":"RNAi in HeLa cells, phosphorylation-dependent Co-IP, immunofluorescence","pmids":["22555603"],"confidence":"Medium","gaps":["Kinase/phosphatase identities not yet defined","Direct vs indirect LBR interaction unresolved at this stage"]},{"year":2013,"claim":"Defined the three-domain architecture, assigning chromatin binding to the disordered C-terminus and NPC anchorage to the β-propeller/α-helical regions.","evidence":"X-ray crystallography (1.9 Å) of β-propeller plus domain deletion analysis","pmids":["23499022"],"confidence":"High","gaps":["Structure of central α-helical and C-terminal regions not solved","Nucleosome contact residues not yet mapped"]},{"year":2016,"claim":"Defined a CDK/SRPK1/2–PP1 phosphorylation network through which ELYS controls LBR localization at the inner nuclear membrane.","evidence":"RNAi, phosphorylation analysis, kinase inhibitors, PP1 depletion","pmids":["27802161"],"confidence":"Medium","gaps":["Whether ELYS scaffolds the kinases/phosphatase directly is unclear","Single-lab evidence"]},{"year":2016,"claim":"Dissected separable ELYS domains for function, localization, chromatin binding, spindle matrix association, and segregation, and revealed an AT-hook checkpoint role.","evidence":"Systematic domain mutagenesis, RNAi, microscopy, genetic epistasis in C. elegans and human cells","pmids":["27341616"],"confidence":"Medium","gaps":["Molecular basis of checkpoint delay not defined","Meiotic role mechanistically open"]},{"year":2017,"claim":"Revealed that RNA is required for proper ELYS chromatin recruitment and downstream import of S-phase kinases, adding an RNA-dependent layer to assembly.","evidence":"Xenopus egg extract with RNA depletion and rescue, fractionation","pmids":["29242643"],"confidence":"Medium","gaps":["Identity of the required RNA(s) unknown","Whether ELYS binds RNA directly not established"]},{"year":2019,"claim":"Provided the structural mechanism of chromatin engagement: the C-terminal RRK stretch binds the nucleosome acidic patch.","evidence":"Cryo-EM, crosslinking MS, mutagenesis, binding assays","pmids":["31069272"],"confidence":"High","gaps":["Relationship between AT-hook DNA binding and acidic-patch binding not integrated","In vivo requirement of RRK not tested in mammals here"]},{"year":2019,"claim":"Established ELYS as a determinant of nuclear size via control of NPC density and nuclear import capacity, rescuable by importin α.","evidence":"High-throughput RNAi, gain/loss-of-function, importin α rescue, nuclear import assay","pmids":["31085625"],"confidence":"Medium","gaps":["Whether size control is separable from pore-seeding function unclear","Importin α as direct vs downstream effector unresolved"]},{"year":2019,"claim":"Connected AHCTF1 to oncogenic transcription by showing it tethers MYC alleles to nuclear pores via β-catenin to accelerate MYC mRNA export.","evidence":"ChIP, gene-gating assays, RNA export measurement, knockdown, β-catenin interaction assays in colon cancer cells","pmids":["31784729"],"confidence":"Medium","gaps":["Directness of AHCTF1–β-catenin contact not fully resolved","Generality beyond MYC/colon cancer untested"]},{"year":2024,"claim":"Identified a mitotic phospho-FFAT motif in ELYS mediating interaction with VAPB at the forming non-core nuclear envelope, linking ELYS to ER membrane proteins during NE reassembly.","evidence":"Reciprocal Co-IP, recombinant binding, mass spectrometry, VAPB depletion phenotypes","pmids":["38605278"],"confidence":"Medium","gaps":["Kinase generating the phospho-FFAT not identified","Functional separation from POM121/NDC1 pathway unclear"]},{"year":null,"claim":"How ELYS coordinates its multiple roles—chromatin seeding, replication licensing, kinetochore function, INM protein organization, and gene gating—into a single regulated program across the cell cycle remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating AT-hook DNA, acidic-patch, and RNA-dependent recruitment","Direct human structural data for full-length protein lacking","Whether disease-relevant mutations exist not addressed in corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,14]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,6,16]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,3,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,15]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13]}],"complexes":["Nup107-160 (Y-complex)","kinetochore"],"partners":["NUP107","POM121","NDC1","LBR","VAPB","MCM2","CTNNB1","NUP37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WYP5","full_name":"Protein ELYS","aliases":["Embryonic large molecule derived from yolk sac","Protein MEL-28","Putative AT-hook-containing transcription factor 1"],"length_aa":2266,"mass_kda":252.5,"function":"Required for the assembly of a functional nuclear pore complex (NPC) on the surface of chromosomes as nuclei form at the end of mitosis. May initiate NPC assembly by binding to chromatin and recruiting the Nup107-160 subcomplex of the NPC. Also required for the localization of the Nup107-160 subcomplex of the NPC to the kinetochore during mitosis and for the completion of cytokinesis","subcellular_location":"Cytoplasm; Nucleus; Nucleus envelope; Nucleus matrix; Chromosome, centromere, kinetochore; Nucleus, nucleoplasm; Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q8WYP5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/AHCTF1","classification":"Common Essential","n_dependent_lines":1198,"n_total_lines":1208,"dependency_fraction":0.9917218543046358},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AHCTF1","total_profiled":1310},"omim":[{"mim_id":"610853","title":"AT-HOOK-CONTAINING TRANSCRIPTION FACTOR 1; AHCTF1","url":"https://www.omim.org/entry/610853"},{"mim_id":"607613","title":"NUCLEOPORIN, 133-KD; NUP133","url":"https://www.omim.org/entry/607613"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AHCTF1"},"hgnc":{"alias_symbol":["ELYS"],"prev_symbol":[]},"alphafold":{"accession":"Q8WYP5","domains":[{"cath_id":"-","chopping":"497-556","consensus_level":"medium","plddt":79.344,"start":497,"end":556},{"cath_id":"-","chopping":"947-1013","consensus_level":"medium","plddt":76.0994,"start":947,"end":1013},{"cath_id":"1.20.58","chopping":"573-687","consensus_level":"medium","plddt":81.3989,"start":573,"end":687}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WYP5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WYP5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WYP5-F1-predicted_aligned_error_v6.png","plddt_mean":54.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AHCTF1","jax_strain_url":"https://www.jax.org/strain/search?query=AHCTF1"},"sequence":{"accession":"Q8WYP5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WYP5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WYP5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WYP5"}},"corpus_meta":[{"pmid":"17098863","id":"PMC_17098863","title":"ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell division.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17098863","citation_count":212,"is_preprint":false},{"pmid":"17235358","id":"PMC_17235358","title":"MEL-28/ELYS is required for the recruitment of nucleoporins to chromatin and postmitotic nuclear pore complex assembly.","date":"2007","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/17235358","citation_count":205,"is_preprint":false},{"pmid":"18596237","id":"PMC_18596237","title":"Capture of AT-rich chromatin by ELYS recruits POM121 and NDC1 to initiate nuclear pore assembly.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18596237","citation_count":134,"is_preprint":false},{"pmid":"17825564","id":"PMC_17825564","title":"ELYS/MEL-28 chromatin association coordinates nuclear pore complex assembly and replication licensing.","date":"2007","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/17825564","citation_count":118,"is_preprint":false},{"pmid":"31784729","id":"PMC_31784729","title":"WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating.","date":"2019","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31784729","citation_count":81,"is_preprint":false},{"pmid":"22955883","id":"PMC_22955883","title":"Molecular basis for Nup37 and ELY5/ELYS recruitment to the nuclear pore complex.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22955883","citation_count":62,"is_preprint":false},{"pmid":"31085625","id":"PMC_31085625","title":"The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity.","date":"2019","source":"EMBO 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nuclear pore formation triggers apoptosis in the intestinal epithelium of elys-deficient zebrafish.","date":"2008","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19073184","citation_count":40,"is_preprint":false},{"pmid":"23499022","id":"PMC_23499022","title":"Structural and functional studies of the 252 kDa nucleoporin ELYS reveal distinct roles for its three tethered domains.","date":"2013","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/23499022","citation_count":36,"is_preprint":false},{"pmid":"11952839","id":"PMC_11952839","title":"Identification of a novel transcription factor, ELYS, expressed predominantly in mouse foetal haematopoietic tissues.","date":"2002","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/11952839","citation_count":32,"is_preprint":false},{"pmid":"15507119","id":"PMC_15507119","title":"Targeted disruption of the mouse ELYS gene results in embryonic death at peri-implantation development.","date":"2004","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/15507119","citation_count":32,"is_preprint":false},{"pmid":"21315719","id":"PMC_21315719","title":"The nuclear pore complex protein Elys is required for genome stability in mouse intestinal epithelial progenitor cells.","date":"2011","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/21315719","citation_count":27,"is_preprint":false},{"pmid":"27802161","id":"PMC_27802161","title":"ELYS regulates the localization of LBR by modulating its phosphorylation state.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27802161","citation_count":24,"is_preprint":false},{"pmid":"31069272","id":"PMC_31069272","title":"Structural and biochemical analyses of the nuclear pore complex component ELYS identify residues responsible for nucleosome binding.","date":"2019","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/31069272","citation_count":16,"is_preprint":false},{"pmid":"29242643","id":"PMC_29242643","title":"RNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29242643","citation_count":10,"is_preprint":false},{"pmid":"31941789","id":"PMC_31941789","title":"Drosophila ELYS regulates Dorsal dynamics during development.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31941789","citation_count":9,"is_preprint":false},{"pmid":"38605278","id":"PMC_38605278","title":"Phosphorylation of ELYS promotes its interaction with VAPB at decondensing chromosomes during mitosis.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38605278","citation_count":6,"is_preprint":false},{"pmid":"12745078","id":"PMC_12745078","title":"Genomic organization and characterization of the mouse ELYS gene.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12745078","citation_count":6,"is_preprint":false},{"pmid":"36648336","id":"PMC_36648336","title":"ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36648336","citation_count":5,"is_preprint":false},{"pmid":"35609608","id":"PMC_35609608","title":"MEL-28/ELYS and CENP-C coordinately control outer kinetochore assembly and meiotic chromosome-microtubule interactions.","date":"2022","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/35609608","citation_count":5,"is_preprint":false},{"pmid":"29773558","id":"PMC_29773558","title":"Genetic Analyses of Elys Mutations in Drosophila Show Maternal-Effect Lethality and Interactions with Nucleoporin Genes.","date":"2018","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29773558","citation_count":5,"is_preprint":false},{"pmid":"32948851","id":"PMC_32948851","title":"Author Correction: WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating.","date":"2020","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32948851","citation_count":4,"is_preprint":false},{"pmid":"40707755","id":"PMC_40707755","title":"AHCTF1 Functions as an Oncogenic Factor and Promotes Tumor Progression in Hepatocellular Carcinoma.","date":"2025","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40707755","citation_count":1,"is_preprint":false},{"pmid":"40359232","id":"PMC_40359232","title":"The Drosophila nucleoporin ELYS is required for parental chromosome arrangement at fertilization.","date":"2025","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/40359232","citation_count":0,"is_preprint":false},{"pmid":"29402910","id":"PMC_29402910","title":"Author Correction: RNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29402910","citation_count":0,"is_preprint":false},{"pmid":"42231458","id":"PMC_42231458","title":"ELYS promotes hepatocellular carcinoma stemness by activating a FOXO6-NUP205 transcriptional module downstream of PI3K/AKT to drive Hedgehog signaling.","date":"2026","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/42231458","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14137,"output_tokens":4340,"usd":0.053755,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12366,"output_tokens":4416,"usd":0.086115,"stage2_stop_reason":"end_turn"},"total_usd":0.13987,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"ELYS co-purifies with the Nup107-160 complex in Xenopus interphase extracts, mitotic extracts, and human cell extracts (co-immunoprecipitation/mass spectrometry), and is required for nuclear pore assembly; RNAi depletion of ELYS in HeLa cells severely disrupts nuclear pores in the nuclear envelope and leads to cytokinesis defects, while lamin, Ran, and tubulin staining appear normal. At mitosis, ELYS targets to kinetochores.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNAi knockdown, immunofluorescence in HeLa cells and Xenopus extracts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with MS identification, RNAi phenotype replicated in multiple systems, multiple orthogonal methods\",\n      \"pmids\": [\"17098863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MEL-28/ELYS (vertebrate homologue) is essential for post-mitotic NPC assembly; it interacts with the Nup107-160 complex and is required for recruitment of the Nup107-160 complex to chromatin, acting as a seeding point for NPC assembly, as demonstrated in in vitro nuclear envelope assembly assays.\",\n      \"method\": \"In vitro nuclear envelope assembly assay, immunodepletion, co-immunoprecipitation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assay with immunodepletion, replicated across labs\",\n      \"pmids\": [\"17235358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ELYS contains an AT-hook domain that binds chromatin with high affinity; this domain competes with full-length ELYS for chromatin association thereby blocking NPC assembly. ELYS also physically associates with the Mcm2-7 replication-licensing proteins on chromatin, and ELYS chromatin loading is delayed when Mcm2-7 is prevented from loading.\",\n      \"method\": \"Xenopus egg extract cell-free system, proteomics, chromatin binding competition assay, co-immunoprecipitation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro chromatin binding, competition assay, physical association by co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17825564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ELYS binds AT-rich chromatin via its AT-hook motif; point mutation of only two amino acids in the AT-hook blocks nuclear pore assembly. Chromatin-bound ELYS/Nup107-160 complex is required for recruitment of vesicles containing integral membrane pore proteins POM121 and NDC1 (but not gp210 vesicles). A direct interaction between the cytoplasmic domain of POM121 and the Nup107-160 complex was identified.\",\n      \"method\": \"Point mutagenesis, DNA-binding antibiotics competition assay, Xenopus in vitro nuclear assembly, co-immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and pharmacological competition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18596237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In zebrafish elys mutants, Elys binds Mcm2-7 complexes from Xenopus egg extracts, and loss of Elys reduces chromatin binding of Mcm2 (but not Mcm3 or Mcm4) in the intestine, indicating a role for Elys in Mcm2-chromatin interactions and replication licensing.\",\n      \"method\": \"Zebrafish genetics (loss-of-function mutation), co-immunoprecipitation with Xenopus extracts, immunofluorescence/immunohistochemistry\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function plus biochemical pulldown, single lab with two orthogonal methods\",\n      \"pmids\": [\"18974873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of S. pombe Nup37 in complex with Nup120 (174-kDa subassembly) was determined; ELY5/ELYS (fission yeast ELYS ortholog) integrates into the Y-complex via Nup120/160 and binds near the Nup120-Nup37 interface, as shown by reconstitution assays and in vivo/in vitro biochemical data.\",\n      \"method\": \"X-ray crystallography (1.9 Å), reconstitution assays, in vivo and in vitro biochemical binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 1.9 Å with reconstitution and mutagenesis; fission yeast ortholog with conserved interactions\",\n      \"pmids\": [\"22955883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ELYS/Mel28 is essential for recruiting the lamin B receptor (LBR) to the chromosomal noncore region during NE reassembly; this depends on Nup107 but not Pom121. ELYS/Mel28 biochemically interacts with LBR in a phosphorylation-dependent manner. ELYS/Mel28 also focuses A-type lamin-binding proteins (emerin, Lap2α, BAF) at the chromosomal core region.\",\n      \"method\": \"RNAi knockdown in HeLa cells, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi knockdown with defined phenotype, co-IP showing phosphorylation-dependent interaction, single lab\",\n      \"pmids\": [\"22555603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ELYS contains three domains: an N-terminal β-propeller domain (crystal structure resolved at 1.9 Å), a central α-helical domain, and a C-terminal disordered region. The disordered C-terminal region is responsible for chromatin interactions, while the β-propeller and α-helical domains synergistically mediate tethering to the NPC. Surface analysis of the β-propeller identifies regions required for NPC anchorage.\",\n      \"method\": \"X-ray crystallography (1.9 Å resolution), domain mapping/deletion analysis, biochemical binding assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with domain deletion functional analysis, single lab with two orthogonal methods\",\n      \"pmids\": [\"23499022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ELYS depletion promotes LBR phosphorylation at CDK- and SRPK1/SRPK2-targeted residues; PP1 phosphatase normally counterbalances this phosphorylation; depletion of PP1 similarly mislocalizes LBR. These results define an ELYS-mediated phosphorylation network controlling LBR localization at the inner nuclear membrane.\",\n      \"method\": \"RNAi knockdown, phosphorylation analysis, kinase inhibitor experiments, PP1 depletion\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional RNAi knockdown with phosphorylation analysis and PP1 epistasis, single lab\",\n      \"pmids\": [\"27802161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MEL-28/ELYS in C. elegans has distinct functional domains: an AT-hook domain required for function (but not localization) whose perturbation delays cell cycle progression in a DNA damage checkpoint-dependent manner; domains for nuclear envelope/kinetochore localization; chromatin binding; mitotic spindle matrix association; and chromosome segregation. A novel meiotic role was also identified.\",\n      \"method\": \"Systematic domain mutagenesis, RNAi, fluorescence microscopy, genetic epistasis in C. elegans and human cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain mutagenesis with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"27341616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNAs are required for proper ELYS recruitment to chromatin during nuclear envelope assembly in Xenopus egg extracts; RNA-depleted extracts show defective ELYS recruitment, impaired NPC assembly, failure in chromatin relaxation, and inability to import/concentrate S-phase kinases needed for DNA replication activation.\",\n      \"method\": \"Xenopus egg extract with RNA depletion, immunofluorescence, biochemical fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with RNA depletion and rescue, single lab\",\n      \"pmids\": [\"29242643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELYS knockdown in human cells results in small nuclei, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import capacity; overexpression of importin α rescues nuclear size and lamin B2 import; ELYS overexpression increases nuclear size, NPC density, and nuclear import. ELYS thus controls nuclear size through regulation of NPC number and nuclear import capacity.\",\n      \"method\": \"High-throughput RNAi screen, importin α overexpression rescue, ELYS overexpression, nuclear import assay, immunofluorescence in mammalian cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with rescue experiment, single lab, multiple readouts\",\n      \"pmids\": [\"31085625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Arg-Arg-Lys (RRK) stretch of the C-terminal ELYS region is essential for nucleosome binding; cryo-EM structure and crosslinking mass spectrometry reveal that the ELYS C-terminal region directly binds the acidic patch of the nucleosome, providing a mechanism for how ELYS engages chromatin to initiate post-mitotic NPC assembly.\",\n      \"method\": \"Cryo-EM structure determination, crosslinking mass spectrometry, mutagenesis, binding assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with crosslinking MS and mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31069272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AHCTF1/ELYS connects nucleoporins to the oncogenic MYC super-enhancer via β-catenin (WNT signaling effector), facilitating tethering of active MYC alleles to nuclear pores to increase transcript export rates, thereby reducing nuclear MYC mRNA degradation and increasing cytoplasmic MYC mRNA levels in colon cancer cells.\",\n      \"method\": \"ChIP, chromatin conformation/gene gating assays, RNA export measurements, AHCTF1 knockdown, β-catenin interaction assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional genomics methods, interaction assays and knockdown, single lab\",\n      \"pmids\": [\"31784729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Drosophila ELYS (dElys) depletion leads to nuclear pore and nuclear lamina assembly defects; genetically, dElys depletion re-activates the Dorsal (NF-κB) pathway during late larval stages, causing ectopic expression of Dorsal target genes and up-regulation of pro-apoptotic genes reaper and hid leading to apoptosis. dElys contains a noncanonical AT-hook-like motif through which it strongly binds DNA.\",\n      \"method\": \"RNAi depletion, fluorescence and electron microscopy, genetic epistasis, quantitative PCR in Drosophila\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with genetic epistasis and defined pathway placement, single lab in Drosophila ortholog\",\n      \"pmids\": [\"31941789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C. elegans oocyte meiosis, MEL-28/ELYS (ortholog of human ELYS) acts in parallel with CENP-C to recruit outer kinetochore components to meiotic chromosomes. MEL-28 also independently links chromosomes to spindle microtubules together with the NDC-80 complex (part of the KMN network), and this function involves the Y-complex nucleoporins that associate with MEL-28. The PP1-docking function shared by MEL-28 and KNL-1 is not involved in microtubule linkage.\",\n      \"method\": \"Genetic epistasis, engineered separation-of-function mutants, RNAi, live imaging in C. elegans\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with engineered mutants and multiple combinations, single lab\",\n      \"pmids\": [\"35609608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"During mitosis, ELYS is phosphorylated at multiple sites including a predicted FFAT motif; this phosphorylation enables interaction with the MSP domain of membrane protein VAPB. In anaphase, ELYS and VAPB co-localize to the non-core region of the newly forming nuclear envelope. VAPB depletion results in prolonged mitosis, slow meta-to-anaphase progression, and chromosome segregation defects.\",\n      \"method\": \"Co-immunoprecipitation, recombinant protein binding assays, mass spectrometry, immunofluorescence, VAPB depletion\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with recombinant proteins, phospho-specific analysis, and knockdown phenotype, single lab\",\n      \"pmids\": [\"38605278\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AHCTF1/ELYS is a large multidomain nucleoporin that initiates post-mitotic nuclear pore complex assembly by binding AT-rich chromatin (and nucleosome acidic patches) via its C-terminal disordered region/RRK stretch, then recruiting the Nup107-160/Y-complex scaffold, which in turn recruits POM121- and NDC1-containing membrane vesicles; it also interacts with Mcm2-7 replication licensing factors on chromatin, controls nuclear size by setting NPC density and nuclear import capacity, localizes to kinetochores during mitosis to ensure chromosome segregation, regulates inner nuclear membrane protein LBR localization through a phosphorylation network involving CDK/SRPK/PP1, interacts with VAPB via a phospho-FFAT motif during mitotic NE reassembly, and in cancer cells connects nucleoporins to WNT/β-catenin-driven oncogenic super-enhancers to facilitate MYC mRNA nuclear export.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AHCTF1 (ELYS/MEL-28) is the seeding nucleoporin that initiates post-mitotic nuclear pore complex (NPC) assembly by linking chromatin to the Nup107-160 (Y-complex) scaffold [#0, #1]. It is a multidomain protein comprising an N-terminal β-propeller, a central α-helical region that together mediate NPC anchorage, and a C-terminal disordered region responsible for chromatin engagement [#7]; this C-terminal region binds AT-rich chromatin through an AT-hook motif and directly contacts the nucleosome acidic patch via its RRK stretch, with point mutations in the AT-hook abolishing NPC assembly [#2, #3, #12]. Chromatin-bound ELYS recruits the Nup107-160 complex, which in turn brings in POM121- and NDC1-containing membrane vesicles to nucleate pores [#1, #3], integrating into the Y-complex at the Nup120/Nup37 interface [#5]. Beyond pore seeding, ELYS sets nuclear size by controlling NPC density and nuclear import capacity, an activity rescuable by importin α [#11], and it organizes inner nuclear membrane proteins during NE reassembly: it recruits the lamin B receptor (LBR) to the chromosomal non-core region through a CDK/SRPK/PP1 phosphorylation network and via a phospho-FFAT–dependent interaction with VAPB [#6, #8, #16]. ELYS also associates with the Mcm2-7 replication-licensing machinery on chromatin, coupling pore assembly to replication competence [#2, #4], and localizes to kinetochores during mitosis where it ensures chromosome segregation [#0, #15]. In colon cancer cells, AHCTF1 tethers active MYC alleles to nuclear pores through β-catenin at WNT-driven super-enhancers, accelerating MYC mRNA export [#13].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that ELYS is a physical and functional partner of the Nup107-160 complex required for nuclear pore assembly, defining its central role at the nuclear envelope.\",\n      \"evidence\": \"Co-IP/MS and RNAi in HeLa cells and Xenopus extracts, with kinetochore targeting at mitosis\",\n      \"pmids\": [\"17098863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of chromatin engagement not yet defined\", \"Direct vs scaffold-mediated kinetochore role unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed ELYS acts upstream as the seeding point that recruits the Nup107-160 complex to chromatin, ordering the NPC assembly pathway.\",\n      \"evidence\": \"In vitro NE assembly assay with immunodepletion and Co-IP\",\n      \"pmids\": [\"17235358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin determinant of recruitment unknown\", \"Membrane vesicle step not yet placed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the AT-hook chromatin-binding domain and linked ELYS to the Mcm2-7 replication-licensing machinery, connecting pore assembly to replication.\",\n      \"evidence\": \"Xenopus egg extract, chromatin binding competition, Co-IP\",\n      \"pmids\": [\"17825564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Mcm2-7 association for replication not established here\", \"Whether interaction is direct unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that AT-hook–mediated chromatin binding is essential for downstream recruitment of POM121/NDC1 membrane vesicles, completing the chromatin-to-membrane assembly chain.\",\n      \"evidence\": \"Point mutagenesis, DNA-binding antibiotic competition, Xenopus in vitro assembly, Co-IP\",\n      \"pmids\": [\"18596237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"gp210 vesicle recruitment pathway distinct and unaddressed\", \"Structural basis of POM121-Y-complex contact unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided in vivo genetic support that Elys promotes Mcm2-chromatin loading, implicating it in replication licensing in an intact organism.\",\n      \"evidence\": \"Zebrafish loss-of-function mutants, Co-IP with Xenopus extracts, immunohistochemistry\",\n      \"pmids\": [\"18974873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for Mcm2 over Mcm3/4 mechanistically unexplained\", \"Cross-species pulldown leaves directness uncertain\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how ELYS integrates structurally into the Y-complex via the Nup120/Nup37 interface.\",\n      \"evidence\": \"X-ray crystallography (1.9 Å) of Nup37–Nup120 with reconstitution and binding assays in fission yeast ortholog\",\n      \"pmids\": [\"22955883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human complex geometry inferred from ortholog\", \"Stoichiometry within assembled NPC not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended ELYS function to inner nuclear membrane organization by showing it recruits LBR and focuses A-type lamin-binding proteins during NE reassembly.\",\n      \"evidence\": \"RNAi in HeLa cells, phosphorylation-dependent Co-IP, immunofluorescence\",\n      \"pmids\": [\"22555603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase/phosphatase identities not yet defined\", \"Direct vs indirect LBR interaction unresolved at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the three-domain architecture, assigning chromatin binding to the disordered C-terminus and NPC anchorage to the β-propeller/α-helical regions.\",\n      \"evidence\": \"X-ray crystallography (1.9 Å) of β-propeller plus domain deletion analysis\",\n      \"pmids\": [\"23499022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of central α-helical and C-terminal regions not solved\", \"Nucleosome contact residues not yet mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a CDK/SRPK1/2–PP1 phosphorylation network through which ELYS controls LBR localization at the inner nuclear membrane.\",\n      \"evidence\": \"RNAi, phosphorylation analysis, kinase inhibitors, PP1 depletion\",\n      \"pmids\": [\"27802161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ELYS scaffolds the kinases/phosphatase directly is unclear\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissected separable ELYS domains for function, localization, chromatin binding, spindle matrix association, and segregation, and revealed an AT-hook checkpoint role.\",\n      \"evidence\": \"Systematic domain mutagenesis, RNAi, microscopy, genetic epistasis in C. elegans and human cells\",\n      \"pmids\": [\"27341616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of checkpoint delay not defined\", \"Meiotic role mechanistically open\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed that RNA is required for proper ELYS chromatin recruitment and downstream import of S-phase kinases, adding an RNA-dependent layer to assembly.\",\n      \"evidence\": \"Xenopus egg extract with RNA depletion and rescue, fractionation\",\n      \"pmids\": [\"29242643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the required RNA(s) unknown\", \"Whether ELYS binds RNA directly not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural mechanism of chromatin engagement: the C-terminal RRK stretch binds the nucleosome acidic patch.\",\n      \"evidence\": \"Cryo-EM, crosslinking MS, mutagenesis, binding assays\",\n      \"pmids\": [\"31069272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between AT-hook DNA binding and acidic-patch binding not integrated\", \"In vivo requirement of RRK not tested in mammals here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established ELYS as a determinant of nuclear size via control of NPC density and nuclear import capacity, rescuable by importin α.\",\n      \"evidence\": \"High-throughput RNAi, gain/loss-of-function, importin α rescue, nuclear import assay\",\n      \"pmids\": [\"31085625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether size control is separable from pore-seeding function unclear\", \"Importin α as direct vs downstream effector unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected AHCTF1 to oncogenic transcription by showing it tethers MYC alleles to nuclear pores via β-catenin to accelerate MYC mRNA export.\",\n      \"evidence\": \"ChIP, gene-gating assays, RNA export measurement, knockdown, β-catenin interaction assays in colon cancer cells\",\n      \"pmids\": [\"31784729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of AHCTF1–β-catenin contact not fully resolved\", \"Generality beyond MYC/colon cancer untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a mitotic phospho-FFAT motif in ELYS mediating interaction with VAPB at the forming non-core nuclear envelope, linking ELYS to ER membrane proteins during NE reassembly.\",\n      \"evidence\": \"Reciprocal Co-IP, recombinant binding, mass spectrometry, VAPB depletion phenotypes\",\n      \"pmids\": [\"38605278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase generating the phospho-FFAT not identified\", \"Functional separation from POM121/NDC1 pathway unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ELYS coordinates its multiple roles—chromatin seeding, replication licensing, kinetochore function, INM protein organization, and gene gating—into a single regulated program across the cell cycle remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating AT-hook DNA, acidic-patch, and RNA-dependent recruitment\", \"Direct human structural data for full-length protein lacking\", \"Whether disease-relevant mutations exist not addressed in corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 14]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 6, 16]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"Nup107-160 (Y-complex)\", \"kinetochore\"],\n    \"partners\": [\"NUP107\", \"POM121\", \"NDC1\", \"LBR\", \"VAPB\", \"MCM2\", \"CTNNB1\", \"NUP37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}