{"gene":"AKAP17A","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1992,"finding":"XE7 (AKAP17A) is a pseudoautosomal gene located at terminal Xp/Yp that escapes X inactivation and is ubiquitously expressed; alternative RNA splicing produces two protein isoforms of 385 and 695 amino acids, where the smaller is a truncated version of the larger resulting from inclusion of a cassette exon introducing an in-frame stop codon.","method":"Northern blot, cDNA/genomic clone sequencing, somatic cell hybrid cDNA library screening","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing of genomic and cDNA clones with functional characterization of alternative splicing, replicated across two independent 1992 papers","pmids":["1302606","1496421"],"is_preprint":false},{"year":2006,"finding":"XE7 (AKAP17A) is an alternative splicing regulator that physically interacts with the SR protein ASF/SF2 and SR-related protein ZNF265 via its arginine/serine (RS)-rich region; it localizes to nuclear speckles where it colocalizes with these splicing factors, and influences alternative splice site selection of CD44, Tra2-beta1, and SRp20 pre-mRNA minigenes.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence colocalization, minigene splicing assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by yeast two-hybrid and Co-IP, nuclear localization by immunofluorescence, functional splicing activity by minigene assays, multiple orthogonal methods in a single focused study","pmids":["16982639"],"is_preprint":false},{"year":2007,"finding":"AKAP17A (SFRS17A/XE7) interacts with the splicing factor ZRANB2 as a novel splicing component; ZRANB2 binds AKAP17A along with essential splicing factors U1-70K and U2AF35.","method":"Protein interaction assay (pulldown/co-immunoprecipitation as described in review of ZRANB2 function)","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — interaction reported in a review-style paper with limited methodological detail in the abstract; single lab, single method implied","pmids":["17905639"],"is_preprint":false},{"year":2023,"finding":"AKAP17A interacts with CAAP1 (a splicing-related protein), and this interaction is involved in the mRNA splicing pathway; overexpression of CAAP1 increased cisplatin sensitivity of platinum-resistant ovarian cancer cells via mRNA splicing through its interaction with AKAP17A.","method":"Immunoprecipitation-mass spectrometry, lentivirus-mediated overexpression, cell viability assay","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — IP-MS identified AKAP17A as CAAP1-interacting protein, functional consequence shown by OE with defined cellular phenotype, but single lab and limited mechanistic detail on AKAP17A's direct role","pmids":["36870674"],"is_preprint":false},{"year":2025,"finding":"AKAP17A is an essential component of 'SOS splicing,' a spliceosome-independent RNA-level defense system that excises DNA transposons from host mRNAs. AKAP17A directly binds TE-containing mRNAs (triggered by base-pairing of inverted terminal repeat elements forming dsRNA hairpins); CAAP1 bridges AKAP17A to the RNA ligase RTCB, allowing RTCB to religate the mRNA fragments generated after TE excision. This function is conserved between C. elegans and human cells.","method":"Genetic loss-of-function (CRISPR/RNAi), RNA binding assays, protein interaction assays, functional mRNA splicing assays in C. elegans and human cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (genetic KO, RNA binding, protein interaction, functional splicing reconstitution), conserved function validated in two organisms, published in peer-reviewed journal with preprint precedent","pmids":["41372403"],"is_preprint":false},{"year":2025,"finding":"AKAP17A is required for HIF1α protein synthesis and HIF1α signaling through a PKA-independent mechanism; depletion of AKAP17A in mammalian cells reduced HIF1α abundance and attenuated transcription of HIF target genes; akap17a-null zebrafish showed impaired hypoxia tolerance and diminished hypoxia-induced erythropoiesis; AKAP17A knockout suppressed cancer cell proliferation in vitro and tumor growth in vivo.","method":"siRNA/CRISPR depletion, zebrafish knockout model, HIF1α protein level measurement, HIF target gene transcriptional assays, in vitro proliferation assays, xenograft tumor models","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mammalian KD, zebrafish KO, in vivo tumor model) with defined molecular (HIF1α protein synthesis) and cellular phenotypes, single lab","pmids":["41391802"],"is_preprint":false},{"year":2025,"finding":"AKAP17A is required for SOS splicing in both C. elegans and human cells: AKAP17A binds TE-containing mRNAs, CAAP1 bridges RTCB and AKAP17A, and RTCB ligates mRNA fragments post-TE excision. This system operates independently of the spliceosome and is triggered by dsRNA hairpin structures formed by inverted terminal repeats of DNA transposons. (Preprint version of the Nature paper.)","method":"Genetic loss-of-function, RNA binding assays, protein interaction assays, functional mRNA splicing assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — same dataset as published Nature paper; preprint corroborates peer-reviewed findings with multiple orthogonal methods across two organisms","pmids":["40027818"],"is_preprint":true}],"current_model":"AKAP17A is a pseudoautosomal, ubiquitously expressed nuclear protein with multiple mechanistic roles: it acts as an SR-related alternative splicing regulator that binds ASF/SF2 and ZNF265 via its RS-rich region to influence splice site selection; it serves as the mRNA-binding component of the spliceosome-independent 'SOS splicing' system, where it recruits CAAP1 and RNA ligase RTCB to excise DNA transposons from host mRNAs and religate the fragments; it interacts with CAAP1 in the context of cisplatin sensitivity via mRNA splicing; and it promotes HIF1α protein synthesis through a PKA-independent mechanism to support hypoxic adaptation and tumor growth."},"narrative":{"mechanistic_narrative":"AKAP17A (originally XE7) is a ubiquitously expressed, X-inactivation-escaping pseudoautosomal nuclear protein that functions at the RNA level, where its arginine/serine (RS)-rich region drives interactions with the splicing machinery [PMID:1302606, PMID:1496421, PMID:16982639]. Through this RS domain it binds the SR protein ASF/SF2 and SR-related protein ZNF265, colocalizes with them in nuclear speckles, and modulates alternative splice site selection [PMID:16982639]. Beyond canonical splicing, AKAP17A is the essential mRNA-binding subunit of 'SOS splicing,' a spliceosome-independent RNA defense system that excises DNA transposons from host transcripts: it directly recognizes TE-containing mRNAs bearing dsRNA hairpins formed by inverted terminal repeats, while CAAP1 bridges AKAP17A to the RNA ligase RTCB, which religates the cleaved mRNA fragments — a function conserved from C. elegans to human cells [PMID:41372403]. The AKAP17A–CAAP1 axis also modulates cisplatin sensitivity in platinum-resistant ovarian cancer cells [PMID:36870674]. AKAP17A additionally supports HIF1α protein synthesis and hypoxic adaptation through a PKA-independent mechanism, and its loss impairs hypoxia tolerance and suppresses tumor growth [PMID:41391802].","teleology":[{"year":1992,"claim":"Establishing the gene's identity and architecture: XE7/AKAP17A was defined as a pseudoautosomal, X-inactivation-escaping gene producing two isoforms via alternative splicing, providing the structural foundation for later functional work.","evidence":"Northern blot, cDNA/genomic clone sequencing, and somatic cell hybrid cDNA library screening","pmids":["1302606","1496421"],"confidence":"High","gaps":["No molecular function assigned at this stage","Functional difference between the 385- and 695-aa isoforms not resolved"]},{"year":2006,"claim":"Assigning a molecular function: the RS-rich region was shown to mediate binding to splicing factors and influence splice site selection, identifying AKAP17A as an alternative splicing regulator localized to nuclear speckles.","evidence":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, and minigene splicing assays for ASF/SF2 and ZNF265","pmids":["16982639"],"confidence":"High","gaps":["Endogenous splicing targets beyond minigene reporters not defined","Whether splicing regulation requires catalytic partners unclear"]},{"year":2007,"claim":"Extending the spliceosomal interactome: AKAP17A was linked to ZRANB2 alongside core splicing factors U1-70K and U2AF35, embedding it in early spliceosome assembly contacts.","evidence":"Protein interaction assay reported within a review of ZRANB2 function","pmids":["17905639"],"confidence":"Medium","gaps":["Limited methodological detail in the abstract/review format","Direct vs. indirect ZRANB2 contact not established"]},{"year":2023,"claim":"Connecting AKAP17A to drug response: its interaction with CAAP1 was implicated in modulating cisplatin sensitivity of resistant ovarian cancer cells through mRNA splicing.","evidence":"IP-mass spectrometry, lentiviral overexpression, and cell viability assays","pmids":["36870674"],"confidence":"Medium","gaps":["AKAP17A's direct mechanistic contribution to the phenotype not isolated","Single lab; splicing events responsible for cisplatin sensitivity not mapped"]},{"year":2025,"claim":"Defining a novel pathway: AKAP17A was identified as the mRNA-binding core of spliceosome-independent SOS splicing, recognizing transposon-derived dsRNA hairpins and recruiting RTCB via CAAP1 to religate cleaved mRNA — a conserved RNA-level transposon defense system.","evidence":"Genetic loss-of-function (CRISPR/RNAi), RNA binding and protein interaction assays, and functional splicing assays in C. elegans and human cells","pmids":["41372403","40027818"],"confidence":"High","gaps":["Structural basis of TE-mRNA recognition by AKAP17A not resolved","Relationship between SOS splicing and canonical SR-mediated splicing function unclear"]},{"year":2025,"claim":"Linking AKAP17A to hypoxic adaptation: it was shown to be required for HIF1α protein synthesis through a PKA-independent mechanism, supporting hypoxia tolerance, erythropoiesis, and tumor growth.","evidence":"siRNA/CRISPR depletion, zebrafish knockout, HIF1α protein and target-gene assays, and xenograft tumor models","pmids":["41391802"],"confidence":"Medium","gaps":["Molecular link between AKAP17A and HIF1α translation not defined","Whether this role depends on its RNA-binding/splicing activity unknown","Single lab"]},{"year":null,"claim":"How AKAP17A's distinct activities — SR-mediated alternative splicing, spliceosome-independent SOS splicing, and HIF1α protein synthesis — are mechanistically connected, and what PKA-related role (if any) underlies its AKAP designation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying molecular model linking the splicing and HIF1α functions","No structural data for any AKAP17A complex","PKA-anchoring role implied by name not characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,4,6]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":["SRSF1","ZNF265","ZRANB2","CAAP1","RTCB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02040","full_name":"A-kinase anchor protein 17A","aliases":["721P","B-lymphocyte antigen","Protein XE7","Protein kinase A-anchoring protein 17A","PRKA17A","Splicing factor, arginine/serine-rich 17A"],"length_aa":695,"mass_kda":80.7,"function":"Splice factor regulating alternative splice site selection for certain mRNA precursors. Mediates regulation of pre-mRNA splicing in a PKA-dependent manner","subcellular_location":"Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q02040/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKAP17A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":74,"dependency_fraction":0.013513513513513514},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AKAP17A","total_profiled":1310},"omim":[{"mim_id":"604347","title":"ZINC FINGER RANBP2-TYPE DOMAIN-CONTAINING PROTEIN 2; ZRANB2","url":"https://www.omim.org/entry/604347"},{"mim_id":"465000","title":"A-KINASE ANCHOR PROTEIN 17A, Y-CHROMOSOMAL; AKAP17A","url":"https://www.omim.org/entry/465000"},{"mim_id":"312095","title":"A-KINASE ANCHOR PROTEIN 17A; AKAP17A","url":"https://www.omim.org/entry/312095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKAP17A"},"hgnc":{"alias_symbol":["XE7","XE7Y","DXYS155E","MGC39904","721P","CCDC133"],"prev_symbol":["CXYorf3","SFRS17A"]},"alphafold":{"accession":"Q02040","domains":[{"cath_id":"3.30.70.330","chopping":"29-117","consensus_level":"high","plddt":89.8899,"start":29,"end":117},{"cath_id":"3.30.70.330","chopping":"125-264","consensus_level":"high","plddt":88.7995,"start":125,"end":264}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02040","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02040-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02040-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKAP17A","jax_strain_url":"https://www.jax.org/strain/search?query=AKAP17A"},"sequence":{"accession":"Q02040","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02040.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02040/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02040"}},"corpus_meta":[{"pmid":"18660847","id":"PMC_18660847","title":"The Human Pseudoautosomal Region (PAR): Origin, Function and Future.","date":"2007","source":"Current genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18660847","citation_count":174,"is_preprint":false},{"pmid":"10747295","id":"PMC_10747295","title":"Expression analysis of thirty one Y chromosome genes in human prostate cancer.","date":"2000","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/10747295","citation_count":81,"is_preprint":false},{"pmid":"29186436","id":"PMC_29186436","title":"Transcriptome profiling of fetal Klinefelter testis tissue reveals a possible involvement of long non-coding RNAs in gonocyte maturation.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29186436","citation_count":40,"is_preprint":false},{"pmid":"1496421","id":"PMC_1496421","title":"Directed isolation of human genes that escape X inactivation.","date":"1992","source":"Somatic cell and molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1496421","citation_count":38,"is_preprint":false},{"pmid":"9736779","id":"PMC_9736779","title":"Gene duplications as a recurrent theme in the evolution of the human pseudoautosomal region 1: isolation of the gene ASMTL.","date":"1998","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9736779","citation_count":35,"is_preprint":false},{"pmid":"36978128","id":"PMC_36978128","title":"X chromosome dosage and the genetic impact across human tissues.","date":"2023","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36978128","citation_count":30,"is_preprint":false},{"pmid":"16982639","id":"PMC_16982639","title":"XE7: a novel splicing factor that interacts with ASF/SF2 and ZNF265.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16982639","citation_count":19,"is_preprint":false},{"pmid":"1302606","id":"PMC_1302606","title":"Structure and expression of the human pseudoautosomal gene XE7.","date":"1992","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1302606","citation_count":18,"is_preprint":false},{"pmid":"32764209","id":"PMC_32764209","title":"Host Genetic and Gut Microbial Signatures in Familial Inflammatory Bowel Disease.","date":"2020","source":"Clinical and translational gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32764209","citation_count":18,"is_preprint":false},{"pmid":"22480294","id":"PMC_22480294","title":"Formulation and characterization of liquid crystal systems containing azelaic acid for topical delivery.","date":"2012","source":"Drug development and industrial pharmacy","url":"https://pubmed.ncbi.nlm.nih.gov/22480294","citation_count":12,"is_preprint":false},{"pmid":"36870674","id":"PMC_36870674","title":"Proteomic analysis reveals CAAP1 negatively correlates with platinum resistance in ovarian cancer.","date":"2023","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/36870674","citation_count":11,"is_preprint":false},{"pmid":"17905639","id":"PMC_17905639","title":"ZRANB2: structural and functional insights into a novel splicing protein.","date":"2007","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17905639","citation_count":11,"is_preprint":false},{"pmid":"29956638","id":"PMC_29956638","title":"Design Graph Theoretical Analysis and In Silico Modeling of Dunaliella Bardawil Biomass Encapsulated N-Succinyl Chitosan Nanoparticles for Enhanced Anticancer Activity.","date":"2018","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29956638","citation_count":10,"is_preprint":false},{"pmid":"1438229","id":"PMC_1438229","title":"Cloning and sequencing of a trophoblast-endothelial-activated lymphocyte surface protein: cDNA sequence and genomic structure.","date":"1992","source":"Proceedings of the National 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of the ASMT Gene for Melatonin Synthesis in Pigs.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39859321","citation_count":0,"is_preprint":false},{"pmid":"41391802","id":"PMC_41391802","title":"A-kinase anchoring protein 17 A promotes hypoxic adaptation and tumor growth by augmenting HIF1α protein synthesis.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41391802","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10656,"output_tokens":2006,"usd":0.031029,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8977,"output_tokens":2439,"usd":0.05293,"stage2_stop_reason":"end_turn"},"total_usd":0.083959,"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\": 1992,\n      \"finding\": \"XE7 (AKAP17A) is a pseudoautosomal gene located at terminal Xp/Yp that escapes X inactivation and is ubiquitously expressed; alternative RNA splicing produces two protein isoforms of 385 and 695 amino acids, where the smaller is a truncated version of the larger resulting from inclusion of a cassette exon introducing an in-frame stop codon.\",\n      \"method\": \"Northern blot, cDNA/genomic clone sequencing, somatic cell hybrid cDNA library screening\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing of genomic and cDNA clones with functional characterization of alternative splicing, replicated across two independent 1992 papers\",\n      \"pmids\": [\"1302606\", \"1496421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"XE7 (AKAP17A) is an alternative splicing regulator that physically interacts with the SR protein ASF/SF2 and SR-related protein ZNF265 via its arginine/serine (RS)-rich region; it localizes to nuclear speckles where it colocalizes with these splicing factors, and influences alternative splice site selection of CD44, Tra2-beta1, and SRp20 pre-mRNA minigenes.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence colocalization, minigene splicing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by yeast two-hybrid and Co-IP, nuclear localization by immunofluorescence, functional splicing activity by minigene assays, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"16982639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AKAP17A (SFRS17A/XE7) interacts with the splicing factor ZRANB2 as a novel splicing component; ZRANB2 binds AKAP17A along with essential splicing factors U1-70K and U2AF35.\",\n      \"method\": \"Protein interaction assay (pulldown/co-immunoprecipitation as described in review of ZRANB2 function)\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction reported in a review-style paper with limited methodological detail in the abstract; single lab, single method implied\",\n      \"pmids\": [\"17905639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AKAP17A interacts with CAAP1 (a splicing-related protein), and this interaction is involved in the mRNA splicing pathway; overexpression of CAAP1 increased cisplatin sensitivity of platinum-resistant ovarian cancer cells via mRNA splicing through its interaction with AKAP17A.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, lentivirus-mediated overexpression, cell viability assay\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — IP-MS identified AKAP17A as CAAP1-interacting protein, functional consequence shown by OE with defined cellular phenotype, but single lab and limited mechanistic detail on AKAP17A's direct role\",\n      \"pmids\": [\"36870674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKAP17A is an essential component of 'SOS splicing,' a spliceosome-independent RNA-level defense system that excises DNA transposons from host mRNAs. AKAP17A directly binds TE-containing mRNAs (triggered by base-pairing of inverted terminal repeat elements forming dsRNA hairpins); CAAP1 bridges AKAP17A to the RNA ligase RTCB, allowing RTCB to religate the mRNA fragments generated after TE excision. This function is conserved between C. elegans and human cells.\",\n      \"method\": \"Genetic loss-of-function (CRISPR/RNAi), RNA binding assays, protein interaction assays, functional mRNA splicing assays in C. elegans and human cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (genetic KO, RNA binding, protein interaction, functional splicing reconstitution), conserved function validated in two organisms, published in peer-reviewed journal with preprint precedent\",\n      \"pmids\": [\"41372403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKAP17A is required for HIF1α protein synthesis and HIF1α signaling through a PKA-independent mechanism; depletion of AKAP17A in mammalian cells reduced HIF1α abundance and attenuated transcription of HIF target genes; akap17a-null zebrafish showed impaired hypoxia tolerance and diminished hypoxia-induced erythropoiesis; AKAP17A knockout suppressed cancer cell proliferation in vitro and tumor growth in vivo.\",\n      \"method\": \"siRNA/CRISPR depletion, zebrafish knockout model, HIF1α protein level measurement, HIF target gene transcriptional assays, in vitro proliferation assays, xenograft tumor models\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mammalian KD, zebrafish KO, in vivo tumor model) with defined molecular (HIF1α protein synthesis) and cellular phenotypes, single lab\",\n      \"pmids\": [\"41391802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKAP17A is required for SOS splicing in both C. elegans and human cells: AKAP17A binds TE-containing mRNAs, CAAP1 bridges RTCB and AKAP17A, and RTCB ligates mRNA fragments post-TE excision. This system operates independently of the spliceosome and is triggered by dsRNA hairpin structures formed by inverted terminal repeats of DNA transposons. (Preprint version of the Nature paper.)\",\n      \"method\": \"Genetic loss-of-function, RNA binding assays, protein interaction assays, functional mRNA splicing assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — same dataset as published Nature paper; preprint corroborates peer-reviewed findings with multiple orthogonal methods across two organisms\",\n      \"pmids\": [\"40027818\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"AKAP17A is a pseudoautosomal, ubiquitously expressed nuclear protein with multiple mechanistic roles: it acts as an SR-related alternative splicing regulator that binds ASF/SF2 and ZNF265 via its RS-rich region to influence splice site selection; it serves as the mRNA-binding component of the spliceosome-independent 'SOS splicing' system, where it recruits CAAP1 and RNA ligase RTCB to excise DNA transposons from host mRNAs and religate the fragments; it interacts with CAAP1 in the context of cisplatin sensitivity via mRNA splicing; and it promotes HIF1α protein synthesis through a PKA-independent mechanism to support hypoxic adaptation and tumor growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AKAP17A (originally XE7) is a ubiquitously expressed, X-inactivation-escaping pseudoautosomal nuclear protein that functions at the RNA level, where its arginine/serine (RS)-rich region drives interactions with the splicing machinery [#0, #1]. Through this RS domain it binds the SR protein ASF/SF2 and SR-related protein ZNF265, colocalizes with them in nuclear speckles, and modulates alternative splice site selection [#1]. Beyond canonical splicing, AKAP17A is the essential mRNA-binding subunit of 'SOS splicing,' a spliceosome-independent RNA defense system that excises DNA transposons from host transcripts: it directly recognizes TE-containing mRNAs bearing dsRNA hairpins formed by inverted terminal repeats, while CAAP1 bridges AKAP17A to the RNA ligase RTCB, which religates the cleaved mRNA fragments — a function conserved from C. elegans to human cells [#4]. The AKAP17A–CAAP1 axis also modulates cisplatin sensitivity in platinum-resistant ovarian cancer cells [#3]. AKAP17A additionally supports HIF1\\u03b1 protein synthesis and hypoxic adaptation through a PKA-independent mechanism, and its loss impairs hypoxia tolerance and suppresses tumor growth [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the gene's identity and architecture: XE7/AKAP17A was defined as a pseudoautosomal, X-inactivation-escaping gene producing two isoforms via alternative splicing, providing the structural foundation for later functional work.\",\n      \"evidence\": \"Northern blot, cDNA/genomic clone sequencing, and somatic cell hybrid cDNA library screening\",\n      \"pmids\": [\"1302606\", \"1496421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular function assigned at this stage\", \"Functional difference between the 385- and 695-aa isoforms not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Assigning a molecular function: the RS-rich region was shown to mediate binding to splicing factors and influence splice site selection, identifying AKAP17A as an alternative splicing regulator localized to nuclear speckles.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, and minigene splicing assays for ASF/SF2 and ZNF265\",\n      \"pmids\": [\"16982639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous splicing targets beyond minigene reporters not defined\", \"Whether splicing regulation requires catalytic partners unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extending the spliceosomal interactome: AKAP17A was linked to ZRANB2 alongside core splicing factors U1-70K and U2AF35, embedding it in early spliceosome assembly contacts.\",\n      \"evidence\": \"Protein interaction assay reported within a review of ZRANB2 function\",\n      \"pmids\": [\"17905639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited methodological detail in the abstract/review format\", \"Direct vs. indirect ZRANB2 contact not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connecting AKAP17A to drug response: its interaction with CAAP1 was implicated in modulating cisplatin sensitivity of resistant ovarian cancer cells through mRNA splicing.\",\n      \"evidence\": \"IP-mass spectrometry, lentiviral overexpression, and cell viability assays\",\n      \"pmids\": [\"36870674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AKAP17A's direct mechanistic contribution to the phenotype not isolated\", \"Single lab; splicing events responsible for cisplatin sensitivity not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining a novel pathway: AKAP17A was identified as the mRNA-binding core of spliceosome-independent SOS splicing, recognizing transposon-derived dsRNA hairpins and recruiting RTCB via CAAP1 to religate cleaved mRNA — a conserved RNA-level transposon defense system.\",\n      \"evidence\": \"Genetic loss-of-function (CRISPR/RNAi), RNA binding and protein interaction assays, and functional splicing assays in C. elegans and human cells\",\n      \"pmids\": [\"41372403\", \"40027818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TE-mRNA recognition by AKAP17A not resolved\", \"Relationship between SOS splicing and canonical SR-mediated splicing function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking AKAP17A to hypoxic adaptation: it was shown to be required for HIF1\\u03b1 protein synthesis through a PKA-independent mechanism, supporting hypoxia tolerance, erythropoiesis, and tumor growth.\",\n      \"evidence\": \"siRNA/CRISPR depletion, zebrafish knockout, HIF1\\u03b1 protein and target-gene assays, and xenograft tumor models\",\n      \"pmids\": [\"41391802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between AKAP17A and HIF1\\u03b1 translation not defined\", \"Whether this role depends on its RNA-binding/splicing activity unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AKAP17A's distinct activities — SR-mediated alternative splicing, spliceosome-independent SOS splicing, and HIF1\\u03b1 protein synthesis — are mechanistically connected, and what PKA-related role (if any) underlies its AKAP designation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying molecular model linking the splicing and HIF1\\u03b1 functions\", \"No structural data for any AKAP17A complex\", \"PKA-anchoring role implied by name not characterized in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRSF1\", \"ZNF265\", \"ZRANB2\", \"CAAP1\", \"RTCB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}