{"gene":"CPSF7","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2010,"finding":"CFIm (including CFIm59/CPSF7) forms stable heterotetramers through dimerization of CFIm25, not simple heterodimers as previously assumed. CFIm68 and CFIm59 are functionally redundant in controlling alternative polyadenylation, but CFIm68 has higher specific activity.","method":"Biochemical purification, co-immunoprecipitation, knockdown experiments, poly(A) site mapping","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown in single lab with multiple orthogonal methods","pmids":["20695905"],"is_preprint":false},{"year":2012,"finding":"Knockdown of CFIm68 and CFIm25, but NOT CFIm59/CPSF7, leads to a transcriptome-wide increase in use of proximal polyadenylation sites in HEK293 cells, indicating CFIm59 does not individually control 3' UTR length globally.","method":"RNA interference knockdown followed by high-throughput poly(A) site mapping","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide functional readout, single lab, negative finding for CFIm59 specifically","pmids":["23187700"],"is_preprint":false},{"year":2017,"finding":"CFIm59/CPSF7 functions as an enhancer-dependent activator of mRNA 3' processing. Its arginine-serine repeat (RS) domain binds specifically to an RS-like region in the CPSF subunit Fip1, and this interaction is inhibited by CFIm68/59 hyper-phosphorylation.","method":"In vitro binding assays, mutagenesis of RS domains, phosphorylation analysis, poly(A) site activation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, binding assays, and genome-wide APA analysis in single rigorous study","pmids":["29276085"],"is_preprint":false},{"year":2018,"finding":"CPSF7 physically interacts with the NS1 protein of influenza A H7N9 virus, as confirmed by co-immunoprecipitation. This interaction is associated with NS1-mediated inhibition of host pre-mRNA polyadenylation.","method":"Co-immunoprecipitation and immunoblotting","journal":"Journal of proteome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP confirmation in single lab, limited mechanistic follow-up for CPSF7 specifically","pmids":["29558158"],"is_preprint":false},{"year":2016,"finding":"HIV-1 capsid recruits the CFIm complex (including CPSF7) in a CPSF6-dependent manner. CPSF5 and CPSF7 appear to facilitate CPSF6 binding to capsid, but CPSF6 incorporation into CFIm is not required for directing preferential HIV-1 integration into genes; CPSF5 and CPSF7 have only minor roles in HIV-1 integration site targeting.","method":"Virologic assays, integration site analysis, CPSF6 variant mutagenesis, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with functional integration site mapping, single lab","pmids":["26994143"],"is_preprint":false},{"year":2021,"finding":"CFIm59/CPSF7 RS domain is required for CFIm-mediated promotion of MAT2A detained intron splicing, revealing a role for CFIm59 in splicing regulation independent of poly(A) site selection.","method":"CRISPR knockout screen, siRNA knockdown, RS domain mutagenesis, RT-PCR splicing assays, SAM metabolite measurement","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (CRISPR screen, mutagenesis, splicing assays, metabolite readout) in single rigorous study","pmids":["33949310"],"is_preprint":false},{"year":2019,"finding":"CPSF7 promotes expression of the WWP2-FL (full-length) isoform, which contains PTEN ubiquitination sites, thereby activating AKT signaling in a PTEN-dependent manner in liver cancer cells. Knockdown of CPSF7 suppresses cell proliferation, migration, and colony formation.","method":"siRNA knockdown, isoform-specific RT-PCR, Western blotting for PTEN/AKT pathway components, cell proliferation and migration assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional assays and pathway readouts in single lab, mechanistic link to WWP2 isoform and PTEN/AKT established","pmids":["31837982"],"is_preprint":false},{"year":2020,"finding":"Stiff matrix downregulates CFIm59/CPSF7 (along with CFIm68 and CFIm25) expression and promotes alternative polyadenylation favoring proximal poly(A) sites in COL1A1 and FN1. Overexpression and knockdown experiments showed CFIm68 and CFIm25 (but not CFIm59 alone) are indispensable for stiff matrix-induced APA and COL1A1 overproduction in human lung fibroblasts.","method":"siRNA knockdown, overexpression, APA analysis, in vivo bleomycin fibrosis model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with APA readout, corroborated in vivo, single lab","pmids":["31935199"],"is_preprint":false},{"year":2022,"finding":"CFIm59/CPSF7 and CFIm68 have distinct, opposing functions in regulating alternative polyadenylation of Pten mRNA and genes in the PI3K/Akt signaling pathway. CFIm59 KO and KD have differential effects on Pten APA compared to CFIm68, with broad transcriptome-wide impacts.","method":"CRISPR KO, siRNA KD, deep sequencing APA analysis, PI3K/Akt pathway analysis in multiple cell lines","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide APA profiling with KO and KD in single lab, multiple cell lines","pmids":["35993810"],"is_preprint":false},{"year":2023,"finding":"CPSF5, but not CPSF7, co-localizes with CPSF6 in biomolecular condensates formed upon HIV-1 nuclear entry, demonstrating that CPSF7 is excluded from CPSF6/CPSF5 HIV-1-induced condensates.","method":"Confocal microscopy, co-localization analysis during HIV-1 infection in T cells and primary macrophages","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single imaging study, negative finding for CPSF7 co-localization, single lab","pmids":["37414787"],"is_preprint":false},{"year":2026,"finding":"CPSF7's RNA recognition motif (RRM) domain is essential for its pre-mRNA cleavage and polyadenylation activity. Splicing factor SNRPD2 regulates CPSF7 levels by promoting inclusion of exon 4 (which encodes part of the RRM); exon 4 skipping introduces premature termination codons and triggers nonsense-mediated decay. CPSF7 preferentially binds distal polyadenylation signals in the UBE2K-201 transcript to maintain its stability.","method":"Splicing analysis, ASO-mediated knockdown, PDX tumor model, iCLIP/RNA-binding assays, NMD pathway analysis, functional cell assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including RNA binding, splicing analysis, in vivo PDX model, single lab","pmids":["42098443"],"is_preprint":false},{"year":2022,"finding":"CPSF7 silencing in lung adenocarcinoma cells inhibits proliferation, migration, and invasion, and blocks AKT/mTOR signaling. Rescue with AKT activator SC79 reverses the antitumor effects of CPSF7 silencing, placing CPSF7 upstream of AKT/mTOR.","method":"siRNA knockdown, overexpression, Western blotting for AKT/mTOR pathway, cell viability and invasion assays, pharmacological rescue","journal":"Open medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by pharmacological rescue without direct molecular mechanism linking CPSF7 to AKT/mTOR","pmids":["36349192"],"is_preprint":false}],"current_model":"CPSF7 (CFIm59) is a large subunit of the heterotetrameric Cleavage Factor Im (CFIm) complex that functions as an enhancer-dependent activator of mRNA 3' processing by binding UGUA-containing poly(A) enhancers; its RS domain directly contacts the CPSF subunit Fip1 (an interaction inhibited by hyper-phosphorylation), and—distinct from its paralog CFIm68—it has opposing/non-redundant roles in regulating alternative polyadenylation of specific transcripts including PTEN and UBE2K, and additionally promotes MAT2A detained intron splicing through its RS domain independently of poly(A) site selection."},"narrative":{"mechanistic_narrative":"CPSF7 (CFIm59) is a large subunit of the heterotetrameric Cleavage Factor Im (CFIm) complex that controls mRNA 3' end processing and alternative polyadenylation (APA) [PMID:20695905, PMID:29276085]. The complex assembles through dimerization of CFIm25, with CFIm59 and its paralog CFIm68 occupying the large-subunit positions [PMID:20695905]. CPSF7 acts as an enhancer-dependent activator of 3' processing, and its arginine-serine (RS) domain directly contacts an RS-like region in the CPSF subunit Fip1, an interaction abolished by CFIm hyper-phosphorylation [PMID:29276085]; its RNA recognition motif is required for cleavage and polyadenylation activity and directs binding to distal poly(A) signals, illustrated by stabilization of the UBE2K-201 transcript [PMID:42098443]. Functionally, CPSF7 is non-redundant with CFIm68: unlike CFIm68 and CFIm25, CFIm59 knockdown does not globally shorten 3' UTRs [PMID:23187700], and the two paralogs exert distinct, opposing effects on APA of Pten and other PI3K/AKT pathway transcripts [PMID:35993810]. Beyond polyadenylation, the CPSF7 RS domain promotes detained-intron splicing of MAT2A independently of poly(A) site selection [PMID:33949310], and CPSF7 levels are themselves controlled post-transcriptionally through SNRPD2-dependent inclusion of the RRM-encoding exon 4, whose skipping triggers nonsense-mediated decay [PMID:42098443]. In cancer cells, CPSF7 promotes proliferation, migration, and AKT signaling, in part by favoring the PTEN-targeting WWP2-FL isoform [PMID:31837982]. CPSF7 is also engaged by viral proteins, physically interacting with influenza A H7N9 NS1 [PMID:29558158] and being recruited with the CFIm complex to HIV-1 capsid in a CPSF6-dependent manner [PMID:26994143].","teleology":[{"year":2010,"claim":"Established the architecture of the CFIm complex and placed CFIm59/CPSF7 as a large subunit within a CFIm25-dimer-based heterotetramer rather than a simple heterodimer.","evidence":"Biochemical purification, reciprocal Co-IP, and knockdown with poly(A) site mapping","pmids":["20695905"],"confidence":"Medium","gaps":["Did not resolve whether CFIm59 and CFIm68 have non-overlapping target sets","No structural detail of subunit contacts"]},{"year":2012,"claim":"Distinguished CFIm59 from other CFIm subunits by showing it does not individually drive global 3' UTR length control, defining its non-redundant role.","evidence":"RNAi knockdown with transcriptome-wide poly(A) site mapping in HEK293 cells","pmids":["23187700"],"confidence":"Medium","gaps":["Negative finding does not identify which transcripts CFIm59 does control","Mechanism of paralog divergence unaddressed"]},{"year":2017,"claim":"Defined the molecular basis for CFIm59 activity by showing its RS domain binds Fip1 to activate enhancer-dependent 3' processing and that phosphorylation gates this contact.","evidence":"In vitro binding assays, RS-domain mutagenesis, phosphorylation analysis, and poly(A) site activation assays","pmids":["29276085"],"confidence":"High","gaps":["Kinase responsible for inhibitory hyper-phosphorylation not identified","Structural model of the RS-Fip1 interface absent"]},{"year":2019,"claim":"Connected CPSF7 to oncogenic signaling by linking it to WWP2-FL isoform expression, PTEN ubiquitination, and AKT activation in liver cancer cells.","evidence":"siRNA knockdown, isoform-specific RT-PCR, PTEN/AKT Western blotting, and proliferation/migration assays","pmids":["31837982"],"confidence":"Medium","gaps":["Direct RNA-binding role of CPSF7 at WWP2 not demonstrated","Whether effect is via APA or splicing unresolved"]},{"year":2020,"claim":"Showed mechanotransduction downregulates CFIm subunits to drive proximal-site APA, but that CFIm59 alone is not indispensable for this fibrotic program.","evidence":"siRNA knockdown, overexpression, APA analysis, and an in vivo bleomycin fibrosis model in lung fibroblasts","pmids":["31935199"],"confidence":"Medium","gaps":["Does not separate CFIm59-specific from complex-level contributions","Upstream signal coupling stiffness to CFIm expression unknown"]},{"year":2021,"claim":"Expanded CPSF7 function beyond polyadenylation by showing its RS domain promotes MAT2A detained-intron splicing independent of poly(A) site choice.","evidence":"CRISPR knockout screen, siRNA knockdown, RS-domain mutagenesis, RT-PCR splicing assays, and SAM metabolite measurement","pmids":["33949310"],"confidence":"High","gaps":["Generality of the splicing role across other detained introns unknown","How the RS domain selects splicing versus polyadenylation contexts unresolved"]},{"year":2022,"claim":"Demonstrated that CFIm59 and CFIm68 have distinct, opposing roles in APA of Pten and PI3K/Akt pathway transcripts, formalizing paralog non-redundancy.","evidence":"CRISPR KO, siRNA KD, deep-sequencing APA profiling, and pathway analysis across multiple cell lines","pmids":["35993810"],"confidence":"Medium","gaps":["Mechanism producing opposing directionality between paralogs not defined","Direct binding-site preferences not mapped"]},{"year":2022,"claim":"Placed CPSF7 upstream of AKT/mTOR signaling in lung adenocarcinoma via pharmacological rescue.","evidence":"siRNA knockdown, overexpression, AKT/mTOR Western blotting, and SC79 rescue of antitumor phenotypes","pmids":["36349192"],"confidence":"Low","gaps":["Pathway placement by rescue without a direct molecular link from CPSF7 to AKT/mTOR","No identified RNA target mediating the effect"]},{"year":2026,"claim":"Defined the RRM as essential for CPSF7 cleavage/polyadenylation activity, identified SNRPD2-controlled exon 4 splicing as an autoregulatory NMD switch, and showed distal poly(A) site binding stabilizes UBE2K transcripts.","evidence":"Splicing analysis, ASO knockdown, iCLIP/RNA-binding assays, NMD pathway analysis, PDX tumor model, and functional cell assays","pmids":["42098443"],"confidence":"Medium","gaps":["Breadth of distal-site preference beyond UBE2K not established","Physiological triggers of SNRPD2-mediated CPSF7 regulation unknown"]},{"year":null,"claim":"How CPSF7 partitions between its polyadenylation, splicing, and isoform-regulatory functions, and what governs its opposing relationship to CFIm68, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CPSF7 within the assembled CFIm complex on RNA","Kinase and signaling inputs controlling RS-domain phosphorylation undefined","Rules distinguishing CFIm59- versus CFIm68-directed APA outcomes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,10]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,5]}],"complexes":["Cleavage Factor Im (CFIm)"],"partners":["CPSF6","NUDT21","FIP1L1","SNRPD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N684","full_name":"Cleavage and polyadenylation specificity factor subunit 7","aliases":["Cleavage and polyadenylation specificity factor 59 kDa subunit","CPSF 59 kDa subunit","Cleavage factor Im complex 59 kDa subunit","CFIm59","Pre-mRNA cleavage factor Im 59 kDa subunit"],"length_aa":471,"mass_kda":52.0,"function":"Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3'-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs (PubMed:17024186, PubMed:29276085, PubMed:8626397). CFIm contributes to the recruitment of multiprotein complexes on specific sequences on the pre-mRNA 3'-end, so called cleavage and polyadenylation signals (pA signals) (PubMed:17024186, PubMed:8626397). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3'-end formation (PubMed:23187700, PubMed:29276085). The CFIm complex acts as a key regulator of cleavage and polyadenylation site choice during APA through its binding to 5'-UGUA-3' elements localized in the 3'-untranslated region (UTR) for a huge number of pre-mRNAs (PubMed:20695905, PubMed:29276085). CPSF7 activates directly the mRNA 3'-processing machinery (PubMed:29276085). Binds to pA signals in RNA substrates (PubMed:17024186, PubMed:8626397)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N684/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPSF7","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":10.0},{"gene":"CLTA","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CPSF7","total_profiled":1310},"omim":[{"mim_id":"621247","title":"CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR 7; CPSF7","url":"https://www.omim.org/entry/621247"},{"mim_id":"604979","title":"CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR 6; CPSF6","url":"https://www.omim.org/entry/604979"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CPSF7"},"hgnc":{"alias_symbol":["FLJ12529","CFIM59"],"prev_symbol":[]},"alphafold":{"accession":"Q8N684","domains":[{"cath_id":"3.30.70.330","chopping":"71-160","consensus_level":"high","plddt":88.6829,"start":71,"end":160},{"cath_id":"-","chopping":"334-407","consensus_level":"high","plddt":93.8823,"start":334,"end":407}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N684","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N684-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N684-F1-predicted_aligned_error_v6.png","plddt_mean":65.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPSF7","jax_strain_url":"https://www.jax.org/strain/search?query=CPSF7"},"sequence":{"accession":"Q8N684","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N684.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N684/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N684"}},"corpus_meta":[{"pmid":"29276085","id":"PMC_29276085","title":"Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29276085","citation_count":179,"is_preprint":false},{"pmid":"23187700","id":"PMC_23187700","title":"Cleavage factor Im is a key regulator of 3' UTR length.","date":"2012","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/23187700","citation_count":131,"is_preprint":false},{"pmid":"23939832","id":"PMC_23939832","title":"MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23939832","citation_count":102,"is_preprint":false},{"pmid":"20695905","id":"PMC_20695905","title":"Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation.","date":"2010","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20695905","citation_count":67,"is_preprint":false},{"pmid":"26994143","id":"PMC_26994143","title":"The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26994143","citation_count":53,"is_preprint":false},{"pmid":"38906115","id":"PMC_38906115","title":"2'-O-methylation at internal sites on mRNA promotes mRNA stability.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38906115","citation_count":51,"is_preprint":false},{"pmid":"33949310","id":"PMC_33949310","title":"SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33949310","citation_count":42,"is_preprint":false},{"pmid":"35202819","id":"PMC_35202819","title":"Piperlongumine synergistically enhances the antitumour activity of sorafenib by mediating ROS-AMPK activation and targeting CPSF7 in liver cancer.","date":"2022","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/35202819","citation_count":31,"is_preprint":false},{"pmid":"31837982","id":"PMC_31837982","title":"CPSF7 regulates liver cancer growth and metastasis by facilitating WWP2-FL and targeting the WWP2/PTEN/AKT signaling pathway.","date":"2019","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31837982","citation_count":27,"is_preprint":false},{"pmid":"31935199","id":"PMC_31935199","title":"Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation.","date":"2020","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31935199","citation_count":24,"is_preprint":false},{"pmid":"29558158","id":"PMC_29558158","title":"Interactome Analysis of NS1 Protein Encoded by Influenza A H7N9 Virus Reveals an Inhibitory Role of NS1 in Host mRNA Maturation.","date":"2018","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/29558158","citation_count":24,"is_preprint":false},{"pmid":"37414787","id":"PMC_37414787","title":"Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection.","date":"2023","source":"Scientific 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of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32486318","citation_count":4,"is_preprint":false},{"pmid":"36349192","id":"PMC_36349192","title":"Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway.","date":"2022","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36349192","citation_count":2,"is_preprint":false},{"pmid":"42098443","id":"PMC_42098443","title":"SNRPD2-CPSF7-UBE2K axis drives ovarian cancer progression via alternative splicing-polyadenylation crosstalk.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/42098443","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13746,"output_tokens":2891,"usd":0.042301,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10122,"output_tokens":3259,"usd":0.066043,"stage2_stop_reason":"end_turn"},"total_usd":0.108344,"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\": 2010,\n      \"finding\": \"CFIm (including CFIm59/CPSF7) forms stable heterotetramers through dimerization of CFIm25, not simple heterodimers as previously assumed. CFIm68 and CFIm59 are functionally redundant in controlling alternative polyadenylation, but CFIm68 has higher specific activity.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, knockdown experiments, poly(A) site mapping\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20695905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of CFIm68 and CFIm25, but NOT CFIm59/CPSF7, leads to a transcriptome-wide increase in use of proximal polyadenylation sites in HEK293 cells, indicating CFIm59 does not individually control 3' UTR length globally.\",\n      \"method\": \"RNA interference knockdown followed by high-throughput poly(A) site mapping\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide functional readout, single lab, negative finding for CFIm59 specifically\",\n      \"pmids\": [\"23187700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CFIm59/CPSF7 functions as an enhancer-dependent activator of mRNA 3' processing. Its arginine-serine repeat (RS) domain binds specifically to an RS-like region in the CPSF subunit Fip1, and this interaction is inhibited by CFIm68/59 hyper-phosphorylation.\",\n      \"method\": \"In vitro binding assays, mutagenesis of RS domains, phosphorylation analysis, poly(A) site activation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, binding assays, and genome-wide APA analysis in single rigorous study\",\n      \"pmids\": [\"29276085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CPSF7 physically interacts with the NS1 protein of influenza A H7N9 virus, as confirmed by co-immunoprecipitation. This interaction is associated with NS1-mediated inhibition of host pre-mRNA polyadenylation.\",\n      \"method\": \"Co-immunoprecipitation and immunoblotting\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirmation in single lab, limited mechanistic follow-up for CPSF7 specifically\",\n      \"pmids\": [\"29558158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HIV-1 capsid recruits the CFIm complex (including CPSF7) in a CPSF6-dependent manner. CPSF5 and CPSF7 appear to facilitate CPSF6 binding to capsid, but CPSF6 incorporation into CFIm is not required for directing preferential HIV-1 integration into genes; CPSF5 and CPSF7 have only minor roles in HIV-1 integration site targeting.\",\n      \"method\": \"Virologic assays, integration site analysis, CPSF6 variant mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with functional integration site mapping, single lab\",\n      \"pmids\": [\"26994143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CFIm59/CPSF7 RS domain is required for CFIm-mediated promotion of MAT2A detained intron splicing, revealing a role for CFIm59 in splicing regulation independent of poly(A) site selection.\",\n      \"method\": \"CRISPR knockout screen, siRNA knockdown, RS domain mutagenesis, RT-PCR splicing assays, SAM metabolite measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (CRISPR screen, mutagenesis, splicing assays, metabolite readout) in single rigorous study\",\n      \"pmids\": [\"33949310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPSF7 promotes expression of the WWP2-FL (full-length) isoform, which contains PTEN ubiquitination sites, thereby activating AKT signaling in a PTEN-dependent manner in liver cancer cells. Knockdown of CPSF7 suppresses cell proliferation, migration, and colony formation.\",\n      \"method\": \"siRNA knockdown, isoform-specific RT-PCR, Western blotting for PTEN/AKT pathway components, cell proliferation and migration assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional assays and pathway readouts in single lab, mechanistic link to WWP2 isoform and PTEN/AKT established\",\n      \"pmids\": [\"31837982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Stiff matrix downregulates CFIm59/CPSF7 (along with CFIm68 and CFIm25) expression and promotes alternative polyadenylation favoring proximal poly(A) sites in COL1A1 and FN1. Overexpression and knockdown experiments showed CFIm68 and CFIm25 (but not CFIm59 alone) are indispensable for stiff matrix-induced APA and COL1A1 overproduction in human lung fibroblasts.\",\n      \"method\": \"siRNA knockdown, overexpression, APA analysis, in vivo bleomycin fibrosis model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with APA readout, corroborated in vivo, single lab\",\n      \"pmids\": [\"31935199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CFIm59/CPSF7 and CFIm68 have distinct, opposing functions in regulating alternative polyadenylation of Pten mRNA and genes in the PI3K/Akt signaling pathway. CFIm59 KO and KD have differential effects on Pten APA compared to CFIm68, with broad transcriptome-wide impacts.\",\n      \"method\": \"CRISPR KO, siRNA KD, deep sequencing APA analysis, PI3K/Akt pathway analysis in multiple cell lines\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide APA profiling with KO and KD in single lab, multiple cell lines\",\n      \"pmids\": [\"35993810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPSF5, but not CPSF7, co-localizes with CPSF6 in biomolecular condensates formed upon HIV-1 nuclear entry, demonstrating that CPSF7 is excluded from CPSF6/CPSF5 HIV-1-induced condensates.\",\n      \"method\": \"Confocal microscopy, co-localization analysis during HIV-1 infection in T cells and primary macrophages\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single imaging study, negative finding for CPSF7 co-localization, single lab\",\n      \"pmids\": [\"37414787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CPSF7's RNA recognition motif (RRM) domain is essential for its pre-mRNA cleavage and polyadenylation activity. Splicing factor SNRPD2 regulates CPSF7 levels by promoting inclusion of exon 4 (which encodes part of the RRM); exon 4 skipping introduces premature termination codons and triggers nonsense-mediated decay. CPSF7 preferentially binds distal polyadenylation signals in the UBE2K-201 transcript to maintain its stability.\",\n      \"method\": \"Splicing analysis, ASO-mediated knockdown, PDX tumor model, iCLIP/RNA-binding assays, NMD pathway analysis, functional cell assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including RNA binding, splicing analysis, in vivo PDX model, single lab\",\n      \"pmids\": [\"42098443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPSF7 silencing in lung adenocarcinoma cells inhibits proliferation, migration, and invasion, and blocks AKT/mTOR signaling. Rescue with AKT activator SC79 reverses the antitumor effects of CPSF7 silencing, placing CPSF7 upstream of AKT/mTOR.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blotting for AKT/mTOR pathway, cell viability and invasion assays, pharmacological rescue\",\n      \"journal\": \"Open medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by pharmacological rescue without direct molecular mechanism linking CPSF7 to AKT/mTOR\",\n      \"pmids\": [\"36349192\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPSF7 (CFIm59) is a large subunit of the heterotetrameric Cleavage Factor Im (CFIm) complex that functions as an enhancer-dependent activator of mRNA 3' processing by binding UGUA-containing poly(A) enhancers; its RS domain directly contacts the CPSF subunit Fip1 (an interaction inhibited by hyper-phosphorylation), and—distinct from its paralog CFIm68—it has opposing/non-redundant roles in regulating alternative polyadenylation of specific transcripts including PTEN and UBE2K, and additionally promotes MAT2A detained intron splicing through its RS domain independently of poly(A) site selection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CPSF7 (CFIm59) is a large subunit of the heterotetrameric Cleavage Factor Im (CFIm) complex that controls mRNA 3' end processing and alternative polyadenylation (APA) [#0, #2]. The complex assembles through dimerization of CFIm25, with CFIm59 and its paralog CFIm68 occupying the large-subunit positions [#0]. CPSF7 acts as an enhancer-dependent activator of 3' processing, and its arginine-serine (RS) domain directly contacts an RS-like region in the CPSF subunit Fip1, an interaction abolished by CFIm hyper-phosphorylation [#2]; its RNA recognition motif is required for cleavage and polyadenylation activity and directs binding to distal poly(A) signals, illustrated by stabilization of the UBE2K-201 transcript [#10]. Functionally, CPSF7 is non-redundant with CFIm68: unlike CFIm68 and CFIm25, CFIm59 knockdown does not globally shorten 3' UTRs [#1], and the two paralogs exert distinct, opposing effects on APA of Pten and other PI3K/AKT pathway transcripts [#8]. Beyond polyadenylation, the CPSF7 RS domain promotes detained-intron splicing of MAT2A independently of poly(A) site selection [#5], and CPSF7 levels are themselves controlled post-transcriptionally through SNRPD2-dependent inclusion of the RRM-encoding exon 4, whose skipping triggers nonsense-mediated decay [#10]. In cancer cells, CPSF7 promotes proliferation, migration, and AKT signaling, in part by favoring the PTEN-targeting WWP2-FL isoform [#6]. CPSF7 is also engaged by viral proteins, physically interacting with influenza A H7N9 NS1 [#3] and being recruited with the CFIm complex to HIV-1 capsid in a CPSF6-dependent manner [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the architecture of the CFIm complex and placed CFIm59/CPSF7 as a large subunit within a CFIm25-dimer-based heterotetramer rather than a simple heterodimer.\",\n      \"evidence\": \"Biochemical purification, reciprocal Co-IP, and knockdown with poly(A) site mapping\",\n      \"pmids\": [\"20695905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve whether CFIm59 and CFIm68 have non-overlapping target sets\", \"No structural detail of subunit contacts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished CFIm59 from other CFIm subunits by showing it does not individually drive global 3' UTR length control, defining its non-redundant role.\",\n      \"evidence\": \"RNAi knockdown with transcriptome-wide poly(A) site mapping in HEK293 cells\",\n      \"pmids\": [\"23187700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative finding does not identify which transcripts CFIm59 does control\", \"Mechanism of paralog divergence unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the molecular basis for CFIm59 activity by showing its RS domain binds Fip1 to activate enhancer-dependent 3' processing and that phosphorylation gates this contact.\",\n      \"evidence\": \"In vitro binding assays, RS-domain mutagenesis, phosphorylation analysis, and poly(A) site activation assays\",\n      \"pmids\": [\"29276085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for inhibitory hyper-phosphorylation not identified\", \"Structural model of the RS-Fip1 interface absent\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected CPSF7 to oncogenic signaling by linking it to WWP2-FL isoform expression, PTEN ubiquitination, and AKT activation in liver cancer cells.\",\n      \"evidence\": \"siRNA knockdown, isoform-specific RT-PCR, PTEN/AKT Western blotting, and proliferation/migration assays\",\n      \"pmids\": [\"31837982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding role of CPSF7 at WWP2 not demonstrated\", \"Whether effect is via APA or splicing unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed mechanotransduction downregulates CFIm subunits to drive proximal-site APA, but that CFIm59 alone is not indispensable for this fibrotic program.\",\n      \"evidence\": \"siRNA knockdown, overexpression, APA analysis, and an in vivo bleomycin fibrosis model in lung fibroblasts\",\n      \"pmids\": [\"31935199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate CFIm59-specific from complex-level contributions\", \"Upstream signal coupling stiffness to CFIm expression unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded CPSF7 function beyond polyadenylation by showing its RS domain promotes MAT2A detained-intron splicing independent of poly(A) site choice.\",\n      \"evidence\": \"CRISPR knockout screen, siRNA knockdown, RS-domain mutagenesis, RT-PCR splicing assays, and SAM metabolite measurement\",\n      \"pmids\": [\"33949310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the splicing role across other detained introns unknown\", \"How the RS domain selects splicing versus polyadenylation contexts unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that CFIm59 and CFIm68 have distinct, opposing roles in APA of Pten and PI3K/Akt pathway transcripts, formalizing paralog non-redundancy.\",\n      \"evidence\": \"CRISPR KO, siRNA KD, deep-sequencing APA profiling, and pathway analysis across multiple cell lines\",\n      \"pmids\": [\"35993810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism producing opposing directionality between paralogs not defined\", \"Direct binding-site preferences not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CPSF7 upstream of AKT/mTOR signaling in lung adenocarcinoma via pharmacological rescue.\",\n      \"evidence\": \"siRNA knockdown, overexpression, AKT/mTOR Western blotting, and SC79 rescue of antitumor phenotypes\",\n      \"pmids\": [\"36349192\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement by rescue without a direct molecular link from CPSF7 to AKT/mTOR\", \"No identified RNA target mediating the effect\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the RRM as essential for CPSF7 cleavage/polyadenylation activity, identified SNRPD2-controlled exon 4 splicing as an autoregulatory NMD switch, and showed distal poly(A) site binding stabilizes UBE2K transcripts.\",\n      \"evidence\": \"Splicing analysis, ASO knockdown, iCLIP/RNA-binding assays, NMD pathway analysis, PDX tumor model, and functional cell assays\",\n      \"pmids\": [\"42098443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of distal-site preference beyond UBE2K not established\", \"Physiological triggers of SNRPD2-mediated CPSF7 regulation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CPSF7 partitions between its polyadenylation, splicing, and isoform-regulatory functions, and what governs its opposing relationship to CFIm68, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CPSF7 within the assembled CFIm complex on RNA\", \"Kinase and signaling inputs controlling RS-domain phosphorylation undefined\", \"Rules distinguishing CFIm59- versus CFIm68-directed APA outcomes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [\"Cleavage Factor Im (CFIm)\"],\n    \"partners\": [\"CPSF6\", \"NUDT21\", \"FIP1L1\", \"SNRPD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}