{"gene":"CAAP1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2011,"finding":"CAAP1 (C9orf82) functions as an anti-apoptotic protein that modulates a caspase-10-dependent mitochondrial caspase-3/9 feedback amplification loop. RNAi knockdown of C9orf82 induced apoptosis associated with activated caspases-3, -8, -9, and -10, and inactivation of caspase-10 or caspase-3 was sufficient to block this apoptosis. Knockdown was associated with increased caspase-10 expression and activation, which was required for generation of an 11 kDa tBid fragment and activation of caspase-9.","method":"RNAi knockdown in A-549 and MCF7/casp3-10b cells, flow cytometry for apoptosis, caspase activity assays, Western blot; genetic rescue via caspase-3/caspase-10 inactivation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and genetic epistasis via caspase inactivation; single lab, multiple orthogonal methods","pmids":["21980415"],"is_preprint":false},{"year":2015,"finding":"Deletion of C9orf82/CAAP1 augments DNA double-strand break (DSB) repair downstream of topoisomerase IIα, thereby sensitizing cells to topoisomerase II poison-induced apoptosis. This was identified in a genome-wide gene knockout screen as an independent factor driving resistance to doxorubicin and etoposide, operating through the DSB repair pathway.","method":"Genome-wide gene knockout screen (haploid cell genetic screen); drug sensitivity assays with doxorubicin and etoposide","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide KO screen with defined cellular phenotype, single lab, pathway placement downstream of Topo IIα","pmids":["26260527"],"is_preprint":false},{"year":2019,"finding":"CRISPR/Cas9 knockout of C9orf82/CAAP1 in mice produced animals born at Mendelian ratios with no overt abnormalities. Primary pre-B cells and MEFs from knockout mice showed comparable sensitivity to DSB-inducing agents (etoposide, doxorubicin) relative to wild-type, and kinetics of γH2AX formation and resolution were indistinguishable between proficient, deficient, and overexpressing MEFs. These data argue against a direct role of CAAP1 in DSB repair or apoptosis regulation in these primary cell contexts.","method":"CRISPR/Cas9 knockout mouse generation, γH2AX assay, drug sensitivity assays in primary pre-B cells and MEFs, class switch recombination analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous in vivo KO model with multiple orthogonal assays; NEGATIVE result against DSB repair and apoptosis roles in primary cells; single lab","pmids":["30629682"],"is_preprint":false},{"year":2023,"finding":"CAAP1 interacts with the splicing factor AKAP17A, and overexpression of CAAP1 increases cisplatin sensitivity of platinum-resistant ovarian cancer cells likely via the mRNA splicing pathway. The interaction was identified by immunoprecipitation-mass spectrometry.","method":"Lentivirus transfection for overexpression, immunoprecipitation-mass spectrometry (IP-MS), drug sensitivity assay in A2780/DDP cells","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — IP-MS identified AKAP17A interaction with functional follow-up; single lab, single study","pmids":["36870674"],"is_preprint":false},{"year":2025,"finding":"CAAP1 is a core component of the SOS splicing system, a spliceosome-independent RNA-level defense that excises DNA transposons from host mRNAs. CAAP1 physically bridges the RNA ligase RTCB and the mRNA-binding protein AKAP17A, allowing RTCB to ligate mRNA fragments generated after transposon excision. This function is conserved in both C. elegans and human cells.","method":"Genetic screen, co-immunoprecipitation/pulldown to identify protein-protein interactions, functional rescue assays, in vivo and in vitro splicing assays in C. elegans and human cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of complex with multiple components, conserved function validated in two organisms (C. elegans and human cells), peer-reviewed in Nature","pmids":["41372403"],"is_preprint":false},{"year":2025,"finding":"CAAP1 bridges RTCB (RNA ligase) and AKAP17A in the SOS splicing complex; this bridging function is required for RTCB-mediated ligation of mRNA fragments after DNA transposon excision from host mRNAs, operating independently of the canonical spliceosome.","method":"Protein interaction studies, genetic requirement tests in C. elegans and human cells, RNA ligation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — preprint corroborating the Nature paper findings; replicated across two organisms; lower confidence assigned because preprint","pmids":["40027818"],"is_preprint":true},{"year":2021,"finding":"Overexpression of CAAP1 in hepatoma cell line SMMC-7721 promoted proliferation, colony formation, migration, and invasion while inhibiting apoptosis; knockdown produced the opposite effects including increased cleaved caspase-3 levels, demonstrating CAAP1 suppresses the intrinsic apoptosis pathway in hepatoma cells.","method":"Overexpression vector and shRNA knockdown in SMMC-7721 cells, CCK-8 proliferation assay, colony formation assay, wound-healing assay, Transwell invasion assay, flow cytometry for apoptosis, Western blot for cleaved caspase-3","journal":"Journal of Sichuan University. Medical science edition","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal functional assays in a single cell line, single lab, no pathway rescue or epistasis","pmids":["34018363"],"is_preprint":false},{"year":2020,"finding":"miR-5100 targets CAAP1 to enhance apoptosis and inhibit autophagy in gastric cancer cells; MKL1 inhibits apoptosis and promotes autophagy by targeting CAAP1 (increasing its expression), and MKL1 also increases miR-5100 expression, forming a regulatory loop.","method":"Western blot, flow cytometry, confocal microscopy for autophagy/apoptosis, in vivo tumor formation in nude mice, miRNA targeting validation","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods including in vivo xenograft, single lab; pathway placement via miRNA-target validation","pmids":["32315812"],"is_preprint":false},{"year":2019,"finding":"miR-135a-5p downregulates CAAP1 expression; overexpression of miR-135a-5p induced apoptosis in hippocampal neurons through repression of CAAP1, reducing cell survival in a temporal lobe epilepsy model.","method":"miR-135a-5p transfection/inhibitor in primary rat hippocampal neurons cultured in magnesium-free medium, flow cytometry for apoptosis, MTT assay, Western blot","journal":"Journal of integrative neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single miRNA-target relationship in one model; limited mechanistic depth","pmids":["31091851"],"is_preprint":false},{"year":2019,"finding":"miR-706 targets CAAP1 to regulate ER stress-initiated cell death; knocking down CAAP1 phenocopied pro-apoptotic effects, and antimiR-706 (which de-represses CAAP1) reduced cell death triggered by ER stress, establishing CAAP1 as a downstream effector in the PERK/ATF4/miR-706 ER stress signaling axis.","method":"miR-706 mimic transfection, lentivirus-mediated shRNA knockdown of PERK and ATF4, CAAP1 knockdown, Annexin V staining for cell death","journal":"Cell journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, multiple knockdowns but limited mechanistic resolution; no direct binding validation","pmids":["31863666"],"is_preprint":false},{"year":2026,"finding":"Phosphoproteomic meta-analysis identified four predominant phosphorylation sites on CAAP1: S203, S89, S312, and T90. Co-regulated phosphosites are enriched in splicing-related processes and spliceosome-related proteins, suggesting CAAP1 phosphorylation may modulate its role in mRNA splicing and apoptosis regulation.","method":"Computational analysis of 885 human phosphoproteomic datasets; enrichment analysis of co-regulated phosphosites","journal":"Omics: a journal of integrative biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatic analysis only, no direct experimental validation of phosphosite function","pmids":["41701571"],"is_preprint":false}],"current_model":"CAAP1 is a conserved anti-apoptotic protein that suppresses caspase-10-dependent mitochondrial apoptosis and, most definitively, serves as a structural bridge between the RNA ligase RTCB and the mRNA-binding protein AKAP17A within the SOS splicing complex — a spliceosome-independent system that excises DNA transposons from host mRNAs to protect gene function — a role conserved across C. elegans and human cells."},"narrative":{"mechanistic_narrative":"CAAP1 is a conserved RNA-processing factor whose best-defined role is as a structural bridge within the SOS splicing system, a spliceosome-independent RNA defense that excises DNA transposons from host mRNAs [PMID:41372403]. CAAP1 physically links the RNA ligase RTCB and the mRNA-binding splicing factor AKAP17A, an arrangement required for RTCB to ligate the mRNA fragments generated after transposon excision, and this function is conserved between C. elegans and human cells [PMID:41372403]. The interaction with AKAP17A was first detected by IP-MS in ovarian cancer cells, where CAAP1 overexpression increased cisplatin sensitivity via the mRNA splicing pathway [PMID:36870674]. Independently of this splicing role, CAAP1 has been characterized as an anti-apoptotic factor: knockdown induces caspase-10-dependent activation of a mitochondrial caspase-3/9 amplification loop involving tBid cleavage [PMID:21980415], and in hepatoma cells CAAP1 suppresses intrinsic apoptosis while promoting proliferation and invasion [PMID:34018363]. CAAP1 was also identified in a haploid knockout screen as a factor whose loss augments DNA double-strand break repair downstream of topoisomerase IIα, sensitizing cells to topoisomerase poisons [PMID:26260527]; however, a CRISPR knockout mouse model showed no defect in DSB repair (γH2AX kinetics) or apoptotic sensitivity in primary pre-B cells and MEFs, arguing against a direct role in these processes in primary cell contexts [PMID:30629682].","teleology":[{"year":2011,"claim":"Established the first functional assignment for CAAP1 as an anti-apoptotic protein, defining how its loss triggers caspase activation rather than leaving the gene a cipher.","evidence":"RNAi knockdown in A-549 and MCF7/casp3-10b cells with caspase activity assays and genetic rescue via caspase-3/-10 inactivation","pmids":["21980415"],"confidence":"Medium","gaps":["No molecular partner or biochemical activity identified for CAAP1 itself","Mechanism of caspase-10 upregulation upon knockdown unresolved","Tested in transformed cell lines only"]},{"year":2015,"claim":"Placed CAAP1 in a DNA-damage context by showing its deletion enhances DSB repair downstream of topoisomerase IIα, linking it to chemoresistance.","evidence":"Genome-wide haploid knockout screen with doxorubicin and etoposide sensitivity assays","pmids":["26260527"],"confidence":"Medium","gaps":["No direct biochemical mechanism connecting CAAP1 to DSB repair machinery","Screen-derived phenotype not validated across cell types"]},{"year":2019,"claim":"An in vivo knockout model directly tested and failed to confirm the proposed DSB-repair and apoptosis roles, sharpening the question of CAAP1's true physiological function.","evidence":"CRISPR/Cas9 knockout mouse with γH2AX kinetics and drug sensitivity assays in primary pre-B cells and MEFs","pmids":["30629682"],"confidence":"Medium","gaps":["Negative result leaves the cell-line phenotypes unexplained (context dependence vs artifact)","Did not assay RNA processing or splicing functions later found to be central"]},{"year":2023,"claim":"Identified the first direct physical partner of CAAP1, AKAP17A, and linked CAAP1 to the mRNA splicing pathway, redirecting the field from apoptosis toward RNA metabolism.","evidence":"IP-MS in platinum-resistant A2780/DDP ovarian cancer cells with overexpression and cisplatin sensitivity assay","pmids":["36870674"],"confidence":"Medium","gaps":["Interaction not reciprocally validated or reconstituted at the time","Mechanism connecting CAAP1-AKAP17A to splicing unresolved in this study"]},{"year":2025,"claim":"Resolved the core molecular mechanism: CAAP1 bridges RTCB and AKAP17A in the SOS splicing complex, enabling spliceosome-independent excision of DNA transposons from host mRNAs, with conservation across two organisms.","evidence":"Genetic screens, co-IP/pulldown, functional rescue, and in vivo/in vitro splicing assays in C. elegans and human cells (Nature; corroborating bioRxiv preprint)","pmids":["41372403","40027818"],"confidence":"High","gaps":["Structural basis of the RTCB-CAAP1-AKAP17A bridge not defined","Relationship between this RNA-ligation role and earlier apoptosis phenotypes unclear"]},{"year":2026,"claim":"Computational phosphoproteomics nominated regulatory phosphosites on CAAP1 co-enriched with splicing machinery, hinting at post-translational control of its RNA role.","evidence":"Meta-analysis of 885 human phosphoproteomic datasets with co-regulation enrichment","pmids":["41701571"],"confidence":"Low","gaps":["Phosphosite function not experimentally validated","No kinase assigned","Functional consequence on splicing or apoptosis untested"]},{"year":null,"claim":"How CAAP1's defined role as an RNA-ligation bridge in the SOS splicing system mechanistically connects to its reported anti-apoptotic activity remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experiment links transposon-excision splicing to caspase regulation","Structure of the SOS complex unknown","Physiological relevance in mammalian tissues beyond cell lines undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,6]}],"complexes":["SOS splicing complex"],"partners":["RTCB","AKAP17A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H8G2","full_name":"Caspase activity and apoptosis inhibitor 1","aliases":["Conserved anti-apoptotic protein","CAAP"],"length_aa":361,"mass_kda":38.4,"function":"Anti-apoptotic protein that modulates a caspase-10 dependent mitochondrial caspase-3/9 feedback amplification loop","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H8G2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAAP1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTN1","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"RBM33","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CAAP1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAAP1"},"hgnc":{"alias_symbol":["FLJ13657","CAAP"],"prev_symbol":["C9orf82"]},"alphafold":{"accession":"Q9H8G2","domains":[{"cath_id":"1.10.1740","chopping":"137-197","consensus_level":"high","plddt":88.201,"start":137,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8G2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8G2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8G2-F1-predicted_aligned_error_v6.png","plddt_mean":61.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAAP1","jax_strain_url":"https://www.jax.org/strain/search?query=CAAP1"},"sequence":{"accession":"Q9H8G2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H8G2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H8G2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8G2"}},"corpus_meta":[{"pmid":"9032303","id":"PMC_9032303","title":"The cellular 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Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/34018363","citation_count":2,"is_preprint":false},{"pmid":"10938515","id":"PMC_10938515","title":"[The role of fungal allergy in bronchial asthma].","date":"2000","source":"Nihon Ishinkin Gakkai zasshi = Japanese journal of medical mycology","url":"https://pubmed.ncbi.nlm.nih.gov/10938515","citation_count":2,"is_preprint":false},{"pmid":"21565689","id":"PMC_21565689","title":"Production and characterisation of monoclonal antibodies against 19-Nortestosterone.","date":"2011","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/21565689","citation_count":2,"is_preprint":false},{"pmid":"41701571","id":"PMC_41701571","title":"Casting the Caspase Activity and Apoptosis Inhibitor 1 Phosphoregulation Through Global Phosphoproteomes.","date":"2026","source":"Omics : a journal of integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/41701571","citation_count":1,"is_preprint":false},{"pmid":"41744490","id":"PMC_41744490","title":"ADAR-mediated tolerance and SOS splicing-mediated excision of transposable elements.","date":"2026","source":"Transcription","url":"https://pubmed.ncbi.nlm.nih.gov/41744490","citation_count":1,"is_preprint":false},{"pmid":"35186067","id":"PMC_35186067","title":"Exploring the Study of miR-1301 Inhibiting the Proliferation and Migration of Squamous Cell Carcinoma YD-38 Cells through PI3K/AKT Pathway under Deep Learning Medical Images.","date":"2022","source":"Computational intelligence and neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35186067","citation_count":1,"is_preprint":false},{"pmid":"30357542","id":"PMC_30357542","title":"Clustered complementary amino acid pairing (CCAAP) for protein-protein interaction.","date":"2018","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30357542","citation_count":1,"is_preprint":false},{"pmid":"41001784","id":"PMC_41001784","title":"Detecting Convergence of Amino Acid Physicochemical Properties Underlying the Organismal Adaptive Convergent Evolution.","date":"2025","source":"Molecular ecology resources","url":"https://pubmed.ncbi.nlm.nih.gov/41001784","citation_count":1,"is_preprint":false},{"pmid":"40933443","id":"PMC_40933443","title":"Clean Air for Asthma and Allergy Programme (CAAP), a randomized controlled trial to evaluate the effectiveness of multicomponent interventions to reduce indoor triggers in childhood asthma.","date":"2025","source":"Asia Pacific allergy","url":"https://pubmed.ncbi.nlm.nih.gov/40933443","citation_count":0,"is_preprint":false},{"pmid":"2029657","id":"PMC_2029657","title":"On the mechanisms of action of PAF on the myocardium.","date":"1991","source":"Bratislavske lekarske listy","url":"https://pubmed.ncbi.nlm.nih.gov/2029657","citation_count":0,"is_preprint":false},{"pmid":"41418472","id":"PMC_41418472","title":"Phase-resolved multi-path drivers of PM2.5 evolution in eastern China under Clean Air Actions and carbon neutrality scenarios.","date":"2025","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/41418472","citation_count":0,"is_preprint":false},{"pmid":"2561348","id":"PMC_2561348","title":"[The blocking action of platelet-activating factor (PAF) on the calcium currents of the atrial fibers in the frog and guinea pig].","date":"1989","source":"Biulleten' eksperimental'noi biologii i meditsiny","url":"https://pubmed.ncbi.nlm.nih.gov/2561348","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30397,"output_tokens":2848,"usd":0.066956,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10162,"output_tokens":2417,"usd":0.055618,"stage2_stop_reason":"end_turn"},"total_usd":0.122574,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CAAP1 (C9orf82) functions as an anti-apoptotic protein that modulates a caspase-10-dependent mitochondrial caspase-3/9 feedback amplification loop. RNAi knockdown of C9orf82 induced apoptosis associated with activated caspases-3, -8, -9, and -10, and inactivation of caspase-10 or caspase-3 was sufficient to block this apoptosis. Knockdown was associated with increased caspase-10 expression and activation, which was required for generation of an 11 kDa tBid fragment and activation of caspase-9.\",\n      \"method\": \"RNAi knockdown in A-549 and MCF7/casp3-10b cells, flow cytometry for apoptosis, caspase activity assays, Western blot; genetic rescue via caspase-3/caspase-10 inactivation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and genetic epistasis via caspase inactivation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21980415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Deletion of C9orf82/CAAP1 augments DNA double-strand break (DSB) repair downstream of topoisomerase IIα, thereby sensitizing cells to topoisomerase II poison-induced apoptosis. This was identified in a genome-wide gene knockout screen as an independent factor driving resistance to doxorubicin and etoposide, operating through the DSB repair pathway.\",\n      \"method\": \"Genome-wide gene knockout screen (haploid cell genetic screen); drug sensitivity assays with doxorubicin and etoposide\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide KO screen with defined cellular phenotype, single lab, pathway placement downstream of Topo IIα\",\n      \"pmids\": [\"26260527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9 knockout of C9orf82/CAAP1 in mice produced animals born at Mendelian ratios with no overt abnormalities. Primary pre-B cells and MEFs from knockout mice showed comparable sensitivity to DSB-inducing agents (etoposide, doxorubicin) relative to wild-type, and kinetics of γH2AX formation and resolution were indistinguishable between proficient, deficient, and overexpressing MEFs. These data argue against a direct role of CAAP1 in DSB repair or apoptosis regulation in these primary cell contexts.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse generation, γH2AX assay, drug sensitivity assays in primary pre-B cells and MEFs, class switch recombination analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous in vivo KO model with multiple orthogonal assays; NEGATIVE result against DSB repair and apoptosis roles in primary cells; single lab\",\n      \"pmids\": [\"30629682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAAP1 interacts with the splicing factor AKAP17A, and overexpression of CAAP1 increases cisplatin sensitivity of platinum-resistant ovarian cancer cells likely via the mRNA splicing pathway. The interaction was identified by immunoprecipitation-mass spectrometry.\",\n      \"method\": \"Lentivirus transfection for overexpression, immunoprecipitation-mass spectrometry (IP-MS), drug sensitivity assay in A2780/DDP cells\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — IP-MS identified AKAP17A interaction with functional follow-up; single lab, single study\",\n      \"pmids\": [\"36870674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAAP1 is a core component of the SOS splicing system, a spliceosome-independent RNA-level defense that excises DNA transposons from host mRNAs. CAAP1 physically bridges the RNA ligase RTCB and the mRNA-binding protein AKAP17A, allowing RTCB to ligate mRNA fragments generated after transposon excision. This function is conserved in both C. elegans and human cells.\",\n      \"method\": \"Genetic screen, co-immunoprecipitation/pulldown to identify protein-protein interactions, functional rescue assays, in vivo and in vitro splicing assays in C. elegans and human cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of complex with multiple components, conserved function validated in two organisms (C. elegans and human cells), peer-reviewed in Nature\",\n      \"pmids\": [\"41372403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAAP1 bridges RTCB (RNA ligase) and AKAP17A in the SOS splicing complex; this bridging function is required for RTCB-mediated ligation of mRNA fragments after DNA transposon excision from host mRNAs, operating independently of the canonical spliceosome.\",\n      \"method\": \"Protein interaction studies, genetic requirement tests in C. elegans and human cells, RNA ligation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — preprint corroborating the Nature paper findings; replicated across two organisms; lower confidence assigned because preprint\",\n      \"pmids\": [\"40027818\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of CAAP1 in hepatoma cell line SMMC-7721 promoted proliferation, colony formation, migration, and invasion while inhibiting apoptosis; knockdown produced the opposite effects including increased cleaved caspase-3 levels, demonstrating CAAP1 suppresses the intrinsic apoptosis pathway in hepatoma cells.\",\n      \"method\": \"Overexpression vector and shRNA knockdown in SMMC-7721 cells, CCK-8 proliferation assay, colony formation assay, wound-healing assay, Transwell invasion assay, flow cytometry for apoptosis, Western blot for cleaved caspase-3\",\n      \"journal\": \"Journal of Sichuan University. Medical science edition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal functional assays in a single cell line, single lab, no pathway rescue or epistasis\",\n      \"pmids\": [\"34018363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-5100 targets CAAP1 to enhance apoptosis and inhibit autophagy in gastric cancer cells; MKL1 inhibits apoptosis and promotes autophagy by targeting CAAP1 (increasing its expression), and MKL1 also increases miR-5100 expression, forming a regulatory loop.\",\n      \"method\": \"Western blot, flow cytometry, confocal microscopy for autophagy/apoptosis, in vivo tumor formation in nude mice, miRNA targeting validation\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods including in vivo xenograft, single lab; pathway placement via miRNA-target validation\",\n      \"pmids\": [\"32315812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-135a-5p downregulates CAAP1 expression; overexpression of miR-135a-5p induced apoptosis in hippocampal neurons through repression of CAAP1, reducing cell survival in a temporal lobe epilepsy model.\",\n      \"method\": \"miR-135a-5p transfection/inhibitor in primary rat hippocampal neurons cultured in magnesium-free medium, flow cytometry for apoptosis, MTT assay, Western blot\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single miRNA-target relationship in one model; limited mechanistic depth\",\n      \"pmids\": [\"31091851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-706 targets CAAP1 to regulate ER stress-initiated cell death; knocking down CAAP1 phenocopied pro-apoptotic effects, and antimiR-706 (which de-represses CAAP1) reduced cell death triggered by ER stress, establishing CAAP1 as a downstream effector in the PERK/ATF4/miR-706 ER stress signaling axis.\",\n      \"method\": \"miR-706 mimic transfection, lentivirus-mediated shRNA knockdown of PERK and ATF4, CAAP1 knockdown, Annexin V staining for cell death\",\n      \"journal\": \"Cell journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, multiple knockdowns but limited mechanistic resolution; no direct binding validation\",\n      \"pmids\": [\"31863666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Phosphoproteomic meta-analysis identified four predominant phosphorylation sites on CAAP1: S203, S89, S312, and T90. Co-regulated phosphosites are enriched in splicing-related processes and spliceosome-related proteins, suggesting CAAP1 phosphorylation may modulate its role in mRNA splicing and apoptosis regulation.\",\n      \"method\": \"Computational analysis of 885 human phosphoproteomic datasets; enrichment analysis of co-regulated phosphosites\",\n      \"journal\": \"Omics: a journal of integrative biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatic analysis only, no direct experimental validation of phosphosite function\",\n      \"pmids\": [\"41701571\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAAP1 is a conserved anti-apoptotic protein that suppresses caspase-10-dependent mitochondrial apoptosis and, most definitively, serves as a structural bridge between the RNA ligase RTCB and the mRNA-binding protein AKAP17A within the SOS splicing complex — a spliceosome-independent system that excises DNA transposons from host mRNAs to protect gene function — a role conserved across C. elegans and human cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAAP1 is a conserved RNA-processing factor whose best-defined role is as a structural bridge within the SOS splicing system, a spliceosome-independent RNA defense that excises DNA transposons from host mRNAs [#4]. CAAP1 physically links the RNA ligase RTCB and the mRNA-binding splicing factor AKAP17A, an arrangement required for RTCB to ligate the mRNA fragments generated after transposon excision, and this function is conserved between C. elegans and human cells [#4]. The interaction with AKAP17A was first detected by IP-MS in ovarian cancer cells, where CAAP1 overexpression increased cisplatin sensitivity via the mRNA splicing pathway [#3]. Independently of this splicing role, CAAP1 has been characterized as an anti-apoptotic factor: knockdown induces caspase-10-dependent activation of a mitochondrial caspase-3/9 amplification loop involving tBid cleavage [#0], and in hepatoma cells CAAP1 suppresses intrinsic apoptosis while promoting proliferation and invasion [#6]. CAAP1 was also identified in a haploid knockout screen as a factor whose loss augments DNA double-strand break repair downstream of topoisomerase IIα, sensitizing cells to topoisomerase poisons [#1]; however, a CRISPR knockout mouse model showed no defect in DSB repair (γH2AX kinetics) or apoptotic sensitivity in primary pre-B cells and MEFs, arguing against a direct role in these processes in primary cell contexts [#2].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the first functional assignment for CAAP1 as an anti-apoptotic protein, defining how its loss triggers caspase activation rather than leaving the gene a cipher.\",\n      \"evidence\": \"RNAi knockdown in A-549 and MCF7/casp3-10b cells with caspase activity assays and genetic rescue via caspase-3/-10 inactivation\",\n      \"pmids\": [\"21980415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or biochemical activity identified for CAAP1 itself\", \"Mechanism of caspase-10 upregulation upon knockdown unresolved\", \"Tested in transformed cell lines only\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed CAAP1 in a DNA-damage context by showing its deletion enhances DSB repair downstream of topoisomerase IIα, linking it to chemoresistance.\",\n      \"evidence\": \"Genome-wide haploid knockout screen with doxorubicin and etoposide sensitivity assays\",\n      \"pmids\": [\"26260527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical mechanism connecting CAAP1 to DSB repair machinery\", \"Screen-derived phenotype not validated across cell types\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"An in vivo knockout model directly tested and failed to confirm the proposed DSB-repair and apoptosis roles, sharpening the question of CAAP1's true physiological function.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mouse with γH2AX kinetics and drug sensitivity assays in primary pre-B cells and MEFs\",\n      \"pmids\": [\"30629682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result leaves the cell-line phenotypes unexplained (context dependence vs artifact)\", \"Did not assay RNA processing or splicing functions later found to be central\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the first direct physical partner of CAAP1, AKAP17A, and linked CAAP1 to the mRNA splicing pathway, redirecting the field from apoptosis toward RNA metabolism.\",\n      \"evidence\": \"IP-MS in platinum-resistant A2780/DDP ovarian cancer cells with overexpression and cisplatin sensitivity assay\",\n      \"pmids\": [\"36870674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not reciprocally validated or reconstituted at the time\", \"Mechanism connecting CAAP1-AKAP17A to splicing unresolved in this study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the core molecular mechanism: CAAP1 bridges RTCB and AKAP17A in the SOS splicing complex, enabling spliceosome-independent excision of DNA transposons from host mRNAs, with conservation across two organisms.\",\n      \"evidence\": \"Genetic screens, co-IP/pulldown, functional rescue, and in vivo/in vitro splicing assays in C. elegans and human cells (Nature; corroborating bioRxiv preprint)\",\n      \"pmids\": [\"41372403\", \"40027818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RTCB-CAAP1-AKAP17A bridge not defined\", \"Relationship between this RNA-ligation role and earlier apoptosis phenotypes unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Computational phosphoproteomics nominated regulatory phosphosites on CAAP1 co-enriched with splicing machinery, hinting at post-translational control of its RNA role.\",\n      \"evidence\": \"Meta-analysis of 885 human phosphoproteomic datasets with co-regulation enrichment\",\n      \"pmids\": [\"41701571\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Phosphosite function not experimentally validated\", \"No kinase assigned\", \"Functional consequence on splicing or apoptosis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAAP1's defined role as an RNA-ligation bridge in the SOS splicing system mechanistically connects to its reported anti-apoptotic activity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experiment links transposon-excision splicing to caspase regulation\", \"Structure of the SOS complex unknown\", \"Physiological relevance in mammalian tissues beyond cell lines undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\"SOS splicing complex\"],\n    \"partners\": [\"RTCB\", \"AKAP17A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}