{"gene":"DNAAF10","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"Monad (WDR92/DNAAF10) is a novel WD40 repeat protein containing only two WD40 repeats; overexpression in HEK293 cells potentiated apoptosis and caspase-3 activation induced by TNF-alpha and cycloheximide, establishing a pro-apoptotic modulatory role.","method":"Overexpression in HEK293 cells, caspase-3 activation assay, apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single overexpression assay in one cell line, single lab, but two orthogonal readouts (apoptosis and caspase-3 activation)","pmids":["16487927"],"is_preprint":false},{"year":2008,"finding":"Monad (WDR92/DNAAF10) physically interacts with RPAP3 (RNA polymerase II-associated protein 3); RPAP3 overexpression potentiated caspase-3 activation and apoptosis induced by TNF-alpha/cycloheximide, and RPAP3 knockdown significantly reduced this apoptosis, placing Monad and RPAP3 in the same apoptosis-modulatory pathway.","method":"Affinity purification and mass spectrometry to identify RPAP3 as Monad-binding protein; RPAP3 overexpression and RNAi knockdown with apoptosis/caspase-3 assays in HEK293 and HeLa cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification/MS for interaction plus functional RNAi rescue, single lab, two orthogonal methods","pmids":["18538670"],"is_preprint":false},{"year":2010,"finding":"PIH1D1, a subunit of the R2TP complex, physically interacts with both RPAP3 and Monad (WDR92/DNAAF10) in HEK293 and U2OS cells; knockdown of PIH1D1 enhanced apoptosis and caspase-3 activation induced by doxorubicin, placing Monad within the R2TP complex as a modulator of apoptosis.","method":"Co-immunoprecipitation; siRNA knockdown with apoptosis and caspase-3 activation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional siRNA knockdown, single lab, two orthogonal methods","pmids":["21078300"],"is_preprint":false},{"year":2013,"finding":"Monad (WDR92/DNAAF10) is an exosome-bound protein that inhibits breast cancer cell invasion by specifically interacting with both the 3'-UTR of amphiregulin mRNA (an EGFR ligand) and the RNA-degrading exosome complex, thereby enhancing amphiregulin mRNA decay; knockdown of Monad increased invasion, which was rescued by anti-amphiregulin neutralizing antibody.","method":"Co-immunoprecipitation of Monad with exosome and with 3'-UTR of amphiregulin mRNA; Monad knockdown invasion assay; neutralizing antibody rescue experiment in MDA-MB-231 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, mRNA decay assay, functional knockdown with antibody rescue), single lab","pmids":["23844004"],"is_preprint":false},{"year":2016,"finding":"WDR92 (DNAAF10) is a cytoplasmic protein required for the correct architectural assembly of motile cilia; RNAi knockdown in planarian Schmidtea mediterranea reduced organismal movement and caused cilia with reduced beat frequency, partial loss of dynein arms, incomplete B-tubule closure, and central pair defects, establishing WDR92 as part of a cytoplasmic chaperone system required to fold key components of motile ciliary axonemes.","method":"RNAi knockdown in planaria; behavioral assay (locomotion); transmission electron microscopy of ciliary ultrastructure; RT-PCR confirmation of knockdown","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi knockdown with defined ultrastructural ciliary phenotype and functional locomotion readout, single lab, multiple orthogonal methods","pmids":["26912790"],"is_preprint":false},{"year":2018,"finding":"WDR92 (DNAAF10) is a component of the PAQosome, a large multisubunit chaperone complex comprising the R2TP complex, the URI1 prefoldin-like complex, RPB5, and WDR92 itself; WDR92 is thus structurally embedded within this chaperone assembly involved in macromolecular complex assembly and stabilization.","method":"Biochemical characterization and complex composition analysis described in review/overview based on prior purification data","journal":"Advances in experimental medicine and biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article summarizing prior biochemical data; no new direct experiment reported in this abstract","pmids":["30484152"],"is_preprint":false},{"year":2019,"finding":"WDR92 (DNAAF10) is a cytoplasmic DNAAF (dynein arm assembly factor) in Chlamydomonas; loss of WDR92 via insertional mutagenesis caused aflagellate cells or cells with stumpy/short flagella and loss of axonemal dynein arms; immunoprecipitation of WDR92 followed by mass spectrometry identified inner dynein arm heavy chains and multiple DNAAFs (RuvBL1, RPAP3, MOT48, ODA7, DYX1C) as binding partners; WDR92 physically interacted with the R2TP-like complex (MOT48-RuvBL1/2-RPAP3) and linked other DNAAFs, indicating WDR92 functions in dynein preassembly in association with the HSP90 co-chaperone R2TP-like complex.","method":"DNA insertional mutagenesis; electron microscopy of axonemal ultrastructure; immunoprecipitation followed by mass spectrometry; co-immunoprecipitation of R2TP-like complex components","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — insertional mutagenesis with ultrastructural phenotype, Co-IP/MS for interaction partners, independently consistent with findings from another lab (PMID 31116681)","pmids":["30428028"],"is_preprint":false},{"year":2019,"finding":"WDR92 (DNAAF10) is specifically required for the cytoplasmic stability of axonemal dynein heavy chains but not IFT dynein heavy chain; a Chlamydomonas wdr92-1 mutant missing the last four WD repeats builds only ~0.7-μm cilia lacking both inner and outer dynein arms; gel filtration of cytoplasmic extracts showed that wdr92-1 extracts almost completely lacked all three outer arm heavy chains while IFT dynein heavy chain was present normally; a wdr92-1 tpg1-2 double mutant built ~7-μm immotile cilia completely lacking dynein arms, indicating WDR92 acts upstream of ciliary transport on cytoplasmic dynein heavy chain folding/stability.","method":"Chlamydomonas mutant characterization; electron microscopy; gel filtration fractionation of cytoplasmic extracts followed by immunoblotting; double mutant epistasis analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro fractionation with biochemical readouts, genetic epistasis (double mutant), ultrastructural phenotyping, consistent with independent findings from another lab (PMID 30428028)","pmids":["31116681"],"is_preprint":false},{"year":2024,"finding":"Genetic dosage of WDR92 (DNAAF10) interacts with DNAAF4/PF23 in Chlamydomonas diploids; double heterozygosity for wdr92 and pf23 showed second-site non-complementation (SSNC) in a protein-synthesis-inhibited sensitized assay, assembling shorter cilia than wild-type; immunoblots showed PF23 protein levels were reduced by half in pf23/wdr92 heterozygotes, indicating that WDR92 dosage influences PF23 stability and that multiple DNAAF gene dosage cooperates to determine ciliary assembly capacity.","method":"Chlamydomonas diploid second-site non-complementation screen; cilia length measurement under cycloheximide-sensitized conditions; immunoblotting for PF23 protein levels","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via SSNC plus immunoblot protein quantification, single lab, two orthogonal methods","pmids":["38498551"],"is_preprint":false}],"current_model":"DNAAF10 (also known as Monad/WDR92) is a conserved cytoplasmic WD-repeat protein that functions as a dynein arm assembly factor (DNAAF), residing within the PAQosome/R2TP-prefoldin-like chaperone complex where it physically associates with RuvBL1/2, RPAP3, and multiple other DNAAFs to stabilize and pre-assemble axonemal dynein heavy chains in the cytoplasm before their transport to the ciliary axoneme; it also modulates apoptosis pathways (via TNF-alpha/caspase-3 signaling in concert with RPAP3 and PIH1D1) and suppresses breast cancer cell invasion by binding amphiregulin mRNA 3'-UTR and promoting its degradation via the RNA exosome."},"narrative":{"mechanistic_narrative":"DNAAF10 (Monad/WDR92) is a conserved cytoplasmic WD40-repeat protein that functions as a dynein arm assembly factor required for the cytoplasmic preassembly of axonemal motors that power motile cilia [PMID:30428028, PMID:31116681]. In Chlamydomonas, loss of WDR92 produces aflagellate or short-flagella cells whose axonemes lack inner and outer dynein arms [PMID:30428028, PMID:31116681], and the protein is specifically required for the cytoplasmic stability of axonemal dynein heavy chains while sparing IFT dynein heavy chain, placing its action upstream of ciliary transport at the level of dynein heavy-chain folding and stability [PMID:31116681]. WDR92 carries out this role as part of an HSP90 co-chaperone system: immunoprecipitation identified inner dynein arm heavy chains together with the R2TP-like complex (RuvBL1, RPAP3, MOT48) and additional DNAAFs (ODA7, DYX1C) as binding partners [PMID:30428028], and its dosage genetically interacts with and stabilizes DNAAF4/PF23 [PMID:38498551]. Consistent with this assembly role, planarian WDR92 knockdown yields cilia with reduced beat frequency, partial loss of dynein arms, and axonemal architectural defects [PMID:26912790]. Independently of ciliary assembly, DNAAF10 was characterized as a modulator of TNF-alpha/cycloheximide-induced caspase-3 activation and apoptosis acting together with its physical partners RPAP3 and PIH1D1 [PMID:16487927, PMID:18538670, PMID:21078300], and as an exosome-bound protein that binds the amphiregulin mRNA 3'-UTR to promote its decay and thereby suppress breast cancer cell invasion [PMID:23844004].","teleology":[{"year":2006,"claim":"Established the first functional readout for an uncharacterized WD40 protein by showing it modulates death signaling, before any ciliary or chaperone role was known.","evidence":"Overexpression in HEK293 cells with TNF-alpha/cycloheximide-induced caspase-3 and apoptosis assays","pmids":["16487927"],"confidence":"Medium","gaps":["Single overexpression assay in one cell line without loss-of-function confirmation","No mechanism linking the protein to caspase activation defined","No endogenous role established"]},{"year":2008,"claim":"Identified the first physical partner, RPAP3, and placed Monad and RPAP3 in a shared apoptosis-modulatory pathway.","evidence":"Affinity purification/MS for interaction plus RPAP3 overexpression and RNAi with apoptosis/caspase-3 assays in HEK293 and HeLa","pmids":["18538670"],"confidence":"Medium","gaps":["Did not place the interaction in the context of a defined chaperone complex","Mechanism by which the RPAP3 association affects caspase-3 unresolved"]},{"year":2010,"claim":"Connected Monad to the R2TP complex by demonstrating interaction with PIH1D1, broadening the protein's partner network beyond RPAP3.","evidence":"Reciprocal Co-IP and siRNA knockdown with doxorubicin-induced apoptosis/caspase-3 assays in HEK293 and U2OS","pmids":["21078300"],"confidence":"Medium","gaps":["Did not link R2TP membership to a substrate or assembly function","Apoptosis modulation mechanism still phenomenological"]},{"year":2013,"claim":"Revealed a distinct post-transcriptional function: directing amphiregulin mRNA decay through the RNA exosome to restrain tumor cell invasion.","evidence":"Co-IP with exosome and with amphiregulin 3'-UTR, knockdown invasion assay with neutralizing-antibody rescue in MDA-MB-231 cells","pmids":["23844004"],"confidence":"Medium","gaps":["Relationship between this RNA-decay role and the chaperone/ciliary roles unknown","Direct RNA binding versus exosome-mediated bridging not resolved","Single cell-line context"]},{"year":2016,"claim":"Provided the first in vivo evidence that WDR92 is required to build motile ciliary axonemes, linking it to dynein arm integrity at the ultrastructural level.","evidence":"RNAi knockdown in planaria with locomotion assay and TEM of ciliary ultrastructure","pmids":["26912790"],"confidence":"Medium","gaps":["Molecular substrate within the axoneme not identified","Cytoplasmic versus axonemal site of action not distinguished"]},{"year":2019,"claim":"Defined WDR92 as a cytoplasmic dynein arm assembly factor acting within an R2TP-like chaperone network alongside dynein heavy chains and other DNAAFs.","evidence":"Insertional mutagenesis with axonemal EM phenotype, IP-MS and Co-IP of R2TP-like components in Chlamydomonas","pmids":["30428028"],"confidence":"High","gaps":["Direct enzymatic/chaperone activity on heavy chains not reconstituted","Order of substrate hand-off among DNAAFs unresolved"]},{"year":2019,"claim":"Pinpointed WDR92's role to the cytoplasmic stability of axonemal dynein heavy chains, acting upstream of ciliary transport and sparing IFT dynein.","evidence":"Chlamydomonas mutant gel-filtration fractionation with immunoblotting, EM, and double-mutant epistasis","pmids":["31116681"],"confidence":"High","gaps":["Biochemical mechanism of heavy-chain folding/stabilization not reconstituted in vitro","Selectivity for axonemal over IFT dynein heavy chain mechanistically unexplained"]},{"year":2024,"claim":"Showed that WDR92 dosage cooperates with another DNAAF (PF23/DNAAF4) and influences its stability, indicating combinatorial control of ciliary assembly capacity.","evidence":"Chlamydomonas diploid second-site non-complementation under cycloheximide sensitization with PF23 immunoblotting","pmids":["38498551"],"confidence":"Medium","gaps":["Direct physical basis for WDR92-dependent PF23 stabilization not shown","Whether the interaction is direct or via shared substrate unclear"]},{"year":null,"claim":"How WDR92/DNAAF10 mechanistically reconciles its cytoplasmic dynein-assembly role with its reported apoptosis-modulatory and mRNA-decay functions, and whether a direct chaperone activity on dynein heavy chains can be reconstituted, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted biochemical assay of WDR92 chaperone activity","No structural model of WDR92 within the PAQosome/R2TP assembly","No human disease linkage established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[6,7]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6,7]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6]}],"complexes":["PAQosome/R2TP-prefoldin-like complex"],"partners":["RPAP3","PIH1D1","RUVBL1","DNAAF4","DYX1C1","MOT48"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MX6","full_name":"Dynein axonemal assembly factor 10","aliases":["WD repeat-containing protein 92","WD repeat-containing protein Monad"],"length_aa":357,"mass_kda":39.7,"function":"Key assembly factor specifically required for the stability of axonemal dynein heavy chains in cytoplasm","subcellular_location":"Dynein axonemal particle","url":"https://www.uniprot.org/uniprotkb/Q96MX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAAF10","classification":"Common Essential","n_dependent_lines":1062,"n_total_lines":1208,"dependency_fraction":0.8791390728476821},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAAF10","total_profiled":1310},"omim":[{"mim_id":"610729","title":"DYNEIN, AXONEMAL, ASSEMBLY FACTOR 10; DNAAF10","url":"https://www.omim.org/entry/610729"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNAAF10"},"hgnc":{"alias_symbol":["FLJ31741","Monad"],"prev_symbol":["WDR92"]},"alphafold":{"accession":"Q96MX6","domains":[{"cath_id":"2.130.10.10","chopping":"7-351","consensus_level":"high","plddt":97.0627,"start":7,"end":351}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MX6-F1-predicted_aligned_error_v6.png","plddt_mean":96.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAAF10","jax_strain_url":"https://www.jax.org/strain/search?query=DNAAF10"},"sequence":{"accession":"Q96MX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MX6"}},"corpus_meta":[{"pmid":"12169566","id":"PMC_12169566","title":"Finding 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overexpression in HEK293 cells potentiated apoptosis and caspase-3 activation induced by TNF-alpha and cycloheximide, establishing a pro-apoptotic modulatory role.\",\n      \"method\": \"Overexpression in HEK293 cells, caspase-3 activation assay, apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single overexpression assay in one cell line, single lab, but two orthogonal readouts (apoptosis and caspase-3 activation)\",\n      \"pmids\": [\"16487927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Monad (WDR92/DNAAF10) physically interacts with RPAP3 (RNA polymerase II-associated protein 3); RPAP3 overexpression potentiated caspase-3 activation and apoptosis induced by TNF-alpha/cycloheximide, and RPAP3 knockdown significantly reduced this apoptosis, placing Monad and RPAP3 in the same apoptosis-modulatory pathway.\",\n      \"method\": \"Affinity purification and mass spectrometry to identify RPAP3 as Monad-binding protein; RPAP3 overexpression and RNAi knockdown with apoptosis/caspase-3 assays in HEK293 and HeLa cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification/MS for interaction plus functional RNAi rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"18538670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PIH1D1, a subunit of the R2TP complex, physically interacts with both RPAP3 and Monad (WDR92/DNAAF10) in HEK293 and U2OS cells; knockdown of PIH1D1 enhanced apoptosis and caspase-3 activation induced by doxorubicin, placing Monad within the R2TP complex as a modulator of apoptosis.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown with apoptosis and caspase-3 activation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional siRNA knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"21078300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Monad (WDR92/DNAAF10) is an exosome-bound protein that inhibits breast cancer cell invasion by specifically interacting with both the 3'-UTR of amphiregulin mRNA (an EGFR ligand) and the RNA-degrading exosome complex, thereby enhancing amphiregulin mRNA decay; knockdown of Monad increased invasion, which was rescued by anti-amphiregulin neutralizing antibody.\",\n      \"method\": \"Co-immunoprecipitation of Monad with exosome and with 3'-UTR of amphiregulin mRNA; Monad knockdown invasion assay; neutralizing antibody rescue experiment in MDA-MB-231 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, mRNA decay assay, functional knockdown with antibody rescue), single lab\",\n      \"pmids\": [\"23844004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR92 (DNAAF10) is a cytoplasmic protein required for the correct architectural assembly of motile cilia; RNAi knockdown in planarian Schmidtea mediterranea reduced organismal movement and caused cilia with reduced beat frequency, partial loss of dynein arms, incomplete B-tubule closure, and central pair defects, establishing WDR92 as part of a cytoplasmic chaperone system required to fold key components of motile ciliary axonemes.\",\n      \"method\": \"RNAi knockdown in planaria; behavioral assay (locomotion); transmission electron microscopy of ciliary ultrastructure; RT-PCR confirmation of knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi knockdown with defined ultrastructural ciliary phenotype and functional locomotion readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26912790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR92 (DNAAF10) is a component of the PAQosome, a large multisubunit chaperone complex comprising the R2TP complex, the URI1 prefoldin-like complex, RPB5, and WDR92 itself; WDR92 is thus structurally embedded within this chaperone assembly involved in macromolecular complex assembly and stabilization.\",\n      \"method\": \"Biochemical characterization and complex composition analysis described in review/overview based on prior purification data\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article summarizing prior biochemical data; no new direct experiment reported in this abstract\",\n      \"pmids\": [\"30484152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR92 (DNAAF10) is a cytoplasmic DNAAF (dynein arm assembly factor) in Chlamydomonas; loss of WDR92 via insertional mutagenesis caused aflagellate cells or cells with stumpy/short flagella and loss of axonemal dynein arms; immunoprecipitation of WDR92 followed by mass spectrometry identified inner dynein arm heavy chains and multiple DNAAFs (RuvBL1, RPAP3, MOT48, ODA7, DYX1C) as binding partners; WDR92 physically interacted with the R2TP-like complex (MOT48-RuvBL1/2-RPAP3) and linked other DNAAFs, indicating WDR92 functions in dynein preassembly in association with the HSP90 co-chaperone R2TP-like complex.\",\n      \"method\": \"DNA insertional mutagenesis; electron microscopy of axonemal ultrastructure; immunoprecipitation followed by mass spectrometry; co-immunoprecipitation of R2TP-like complex components\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — insertional mutagenesis with ultrastructural phenotype, Co-IP/MS for interaction partners, independently consistent with findings from another lab (PMID 31116681)\",\n      \"pmids\": [\"30428028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR92 (DNAAF10) is specifically required for the cytoplasmic stability of axonemal dynein heavy chains but not IFT dynein heavy chain; a Chlamydomonas wdr92-1 mutant missing the last four WD repeats builds only ~0.7-μm cilia lacking both inner and outer dynein arms; gel filtration of cytoplasmic extracts showed that wdr92-1 extracts almost completely lacked all three outer arm heavy chains while IFT dynein heavy chain was present normally; a wdr92-1 tpg1-2 double mutant built ~7-μm immotile cilia completely lacking dynein arms, indicating WDR92 acts upstream of ciliary transport on cytoplasmic dynein heavy chain folding/stability.\",\n      \"method\": \"Chlamydomonas mutant characterization; electron microscopy; gel filtration fractionation of cytoplasmic extracts followed by immunoblotting; double mutant epistasis analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro fractionation with biochemical readouts, genetic epistasis (double mutant), ultrastructural phenotyping, consistent with independent findings from another lab (PMID 30428028)\",\n      \"pmids\": [\"31116681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genetic dosage of WDR92 (DNAAF10) interacts with DNAAF4/PF23 in Chlamydomonas diploids; double heterozygosity for wdr92 and pf23 showed second-site non-complementation (SSNC) in a protein-synthesis-inhibited sensitized assay, assembling shorter cilia than wild-type; immunoblots showed PF23 protein levels were reduced by half in pf23/wdr92 heterozygotes, indicating that WDR92 dosage influences PF23 stability and that multiple DNAAF gene dosage cooperates to determine ciliary assembly capacity.\",\n      \"method\": \"Chlamydomonas diploid second-site non-complementation screen; cilia length measurement under cycloheximide-sensitized conditions; immunoblotting for PF23 protein levels\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via SSNC plus immunoblot protein quantification, single lab, two orthogonal methods\",\n      \"pmids\": [\"38498551\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAAF10 (also known as Monad/WDR92) is a conserved cytoplasmic WD-repeat protein that functions as a dynein arm assembly factor (DNAAF), residing within the PAQosome/R2TP-prefoldin-like chaperone complex where it physically associates with RuvBL1/2, RPAP3, and multiple other DNAAFs to stabilize and pre-assemble axonemal dynein heavy chains in the cytoplasm before their transport to the ciliary axoneme; it also modulates apoptosis pathways (via TNF-alpha/caspase-3 signaling in concert with RPAP3 and PIH1D1) and suppresses breast cancer cell invasion by binding amphiregulin mRNA 3'-UTR and promoting its degradation via the RNA exosome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAAF10 (Monad/WDR92) is a conserved cytoplasmic WD40-repeat protein that functions as a dynein arm assembly factor required for the cytoplasmic preassembly of axonemal motors that power motile cilia [#6, #7]. In Chlamydomonas, loss of WDR92 produces aflagellate or short-flagella cells whose axonemes lack inner and outer dynein arms [#6, #7], and the protein is specifically required for the cytoplasmic stability of axonemal dynein heavy chains while sparing IFT dynein heavy chain, placing its action upstream of ciliary transport at the level of dynein heavy-chain folding and stability [#7]. WDR92 carries out this role as part of an HSP90 co-chaperone system: immunoprecipitation identified inner dynein arm heavy chains together with the R2TP-like complex (RuvBL1, RPAP3, MOT48) and additional DNAAFs (ODA7, DYX1C) as binding partners [#6], and its dosage genetically interacts with and stabilizes DNAAF4/PF23 [#8]. Consistent with this assembly role, planarian WDR92 knockdown yields cilia with reduced beat frequency, partial loss of dynein arms, and axonemal architectural defects [#4]. Independently of ciliary assembly, DNAAF10 was characterized as a modulator of TNF-alpha/cycloheximide-induced caspase-3 activation and apoptosis acting together with its physical partners RPAP3 and PIH1D1 [#0, #1, #2], and as an exosome-bound protein that binds the amphiregulin mRNA 3'-UTR to promote its decay and thereby suppress breast cancer cell invasion [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first functional readout for an uncharacterized WD40 protein by showing it modulates death signaling, before any ciliary or chaperone role was known.\",\n      \"evidence\": \"Overexpression in HEK293 cells with TNF-alpha/cycloheximide-induced caspase-3 and apoptosis assays\",\n      \"pmids\": [\"16487927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single overexpression assay in one cell line without loss-of-function confirmation\",\n        \"No mechanism linking the protein to caspase activation defined\",\n        \"No endogenous role established\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first physical partner, RPAP3, and placed Monad and RPAP3 in a shared apoptosis-modulatory pathway.\",\n      \"evidence\": \"Affinity purification/MS for interaction plus RPAP3 overexpression and RNAi with apoptosis/caspase-3 assays in HEK293 and HeLa\",\n      \"pmids\": [\"18538670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not place the interaction in the context of a defined chaperone complex\",\n        \"Mechanism by which the RPAP3 association affects caspase-3 unresolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected Monad to the R2TP complex by demonstrating interaction with PIH1D1, broadening the protein's partner network beyond RPAP3.\",\n      \"evidence\": \"Reciprocal Co-IP and siRNA knockdown with doxorubicin-induced apoptosis/caspase-3 assays in HEK293 and U2OS\",\n      \"pmids\": [\"21078300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not link R2TP membership to a substrate or assembly function\",\n        \"Apoptosis modulation mechanism still phenomenological\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a distinct post-transcriptional function: directing amphiregulin mRNA decay through the RNA exosome to restrain tumor cell invasion.\",\n      \"evidence\": \"Co-IP with exosome and with amphiregulin 3'-UTR, knockdown invasion assay with neutralizing-antibody rescue in MDA-MB-231 cells\",\n      \"pmids\": [\"23844004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relationship between this RNA-decay role and the chaperone/ciliary roles unknown\",\n        \"Direct RNA binding versus exosome-mediated bridging not resolved\",\n        \"Single cell-line context\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the first in vivo evidence that WDR92 is required to build motile ciliary axonemes, linking it to dynein arm integrity at the ultrastructural level.\",\n      \"evidence\": \"RNAi knockdown in planaria with locomotion assay and TEM of ciliary ultrastructure\",\n      \"pmids\": [\"26912790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular substrate within the axoneme not identified\",\n        \"Cytoplasmic versus axonemal site of action not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined WDR92 as a cytoplasmic dynein arm assembly factor acting within an R2TP-like chaperone network alongside dynein heavy chains and other DNAAFs.\",\n      \"evidence\": \"Insertional mutagenesis with axonemal EM phenotype, IP-MS and Co-IP of R2TP-like components in Chlamydomonas\",\n      \"pmids\": [\"30428028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct enzymatic/chaperone activity on heavy chains not reconstituted\",\n        \"Order of substrate hand-off among DNAAFs unresolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed WDR92's role to the cytoplasmic stability of axonemal dynein heavy chains, acting upstream of ciliary transport and sparing IFT dynein.\",\n      \"evidence\": \"Chlamydomonas mutant gel-filtration fractionation with immunoblotting, EM, and double-mutant epistasis\",\n      \"pmids\": [\"31116681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical mechanism of heavy-chain folding/stabilization not reconstituted in vitro\",\n        \"Selectivity for axonemal over IFT dynein heavy chain mechanistically unexplained\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that WDR92 dosage cooperates with another DNAAF (PF23/DNAAF4) and influences its stability, indicating combinatorial control of ciliary assembly capacity.\",\n      \"evidence\": \"Chlamydomonas diploid second-site non-complementation under cycloheximide sensitization with PF23 immunoblotting\",\n      \"pmids\": [\"38498551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical basis for WDR92-dependent PF23 stabilization not shown\",\n        \"Whether the interaction is direct or via shared substrate unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR92/DNAAF10 mechanistically reconciles its cytoplasmic dynein-assembly role with its reported apoptosis-modulatory and mRNA-decay functions, and whether a direct chaperone activity on dynein heavy chains can be reconstituted, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstituted biochemical assay of WDR92 chaperone activity\",\n        \"No structural model of WDR92 within the PAQosome/R2TP assembly\",\n        \"No human disease linkage established in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"PAQosome/R2TP-prefoldin-like complex\"\n    ],\n    \"partners\": [\n      \"RPAP3\",\n      \"PIH1D1\",\n      \"RuvBL1\",\n      \"DNAAF4\",\n      \"DYX1C1\",\n      \"MOT48\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}