Affinage

CPSF7

Cleavage and polyadenylation specificity factor subunit 7 · UniProt Q8N684

Length
471 aa
Mass
52.0 kDa
Annotated
2026-06-09
24 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    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

    PMID:20695905

    Open questions at the time
    • Did not resolve whether CFIm59 and CFIm68 have non-overlapping target sets
    • No structural detail of subunit contacts
  2. 2012 Medium

    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

    PMID:23187700

    Open questions at the time
    • Negative finding does not identify which transcripts CFIm59 does control
    • Mechanism of paralog divergence unaddressed
  3. 2017 High

    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

    PMID:29276085

    Open questions at the time
    • Kinase responsible for inhibitory hyper-phosphorylation not identified
    • Structural model of the RS-Fip1 interface absent
  4. 2019 Medium

    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

    PMID:31837982

    Open questions at the time
    • Direct RNA-binding role of CPSF7 at WWP2 not demonstrated
    • Whether effect is via APA or splicing unresolved
  5. 2020 Medium

    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

    PMID:31935199

    Open questions at the time
    • Does not separate CFIm59-specific from complex-level contributions
    • Upstream signal coupling stiffness to CFIm expression unknown
  6. 2021 High

    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

    PMID:33949310

    Open questions at the time
    • Generality of the splicing role across other detained introns unknown
    • How the RS domain selects splicing versus polyadenylation contexts unresolved
  7. 2022 Medium

    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

    PMID:35993810

    Open questions at the time
    • Mechanism producing opposing directionality between paralogs not defined
    • Direct binding-site preferences not mapped
  8. 2022 Low

    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

    PMID:36349192

    Open questions at the time
    • Pathway placement by rescue without a direct molecular link from CPSF7 to AKT/mTOR
    • No identified RNA target mediating the effect
  9. 2026 Medium

    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

    PMID:42098443

    Open questions at the time
    • Breadth of distal-site preference beyond UBE2K not established
    • Physiological triggers of SNRPD2-mediated CPSF7 regulation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CPSF7 partitions between its polyadenylation, splicing, and isoform-regulatory functions, and what governs its opposing relationship to CFIm68, remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
CPSF6FIP1L1NUDT21SNRPD2
Complex memberships
Cleavage Factor Im (CFIm)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Biochemical purification, co-immunoprecipitation, knockdown experiments, poly(A) site mapping Genes to cells Medium 20695905
2012 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. RNA interference knockdown followed by high-throughput poly(A) site mapping RNA biology Medium 23187700
2017 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. In vitro binding assays, mutagenesis of RS domains, phosphorylation analysis, poly(A) site activation assays Molecular cell High 29276085
2018 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. Co-immunoprecipitation and immunoblotting Journal of proteome research Low 29558158
2016 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. Virologic assays, integration site analysis, CPSF6 variant mutagenesis, co-immunoprecipitation The Journal of biological chemistry Medium 26994143
2021 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. CRISPR knockout screen, siRNA knockdown, RS domain mutagenesis, RT-PCR splicing assays, SAM metabolite measurement eLife High 33949310
2019 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. siRNA knockdown, isoform-specific RT-PCR, Western blotting for PTEN/AKT pathway components, cell proliferation and migration assays Biochimica et biophysica acta. Molecular cell research Medium 31837982
2020 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. siRNA knockdown, overexpression, APA analysis, in vivo bleomycin fibrosis model JCI insight Medium 31935199
2022 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. CRISPR KO, siRNA KD, deep sequencing APA analysis, PI3K/Akt pathway analysis in multiple cell lines Nucleic acids research Medium 35993810
2023 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. Confocal microscopy, co-localization analysis during HIV-1 infection in T cells and primary macrophages Scientific reports Low 37414787
2026 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. Splicing analysis, ASO-mediated knockdown, PDX tumor model, iCLIP/RNA-binding assays, NMD pathway analysis, functional cell assays Oncogene Medium 42098443
2022 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. siRNA knockdown, overexpression, Western blotting for AKT/mTOR pathway, cell viability and invasion assays, pharmacological rescue Open medicine Low 36349192

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation. Molecular cell 179 29276085
2012 Cleavage factor Im is a key regulator of 3' UTR length. RNA biology 131 23187700
2013 MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion. The Journal of pathology 102 23939832
2010 Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation. Genes to cells : devoted to molecular & cellular mechanisms 67 20695905
2016 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. The Journal of biological chemistry 53 26994143
2024 2'-O-methylation at internal sites on mRNA promotes mRNA stability. Molecular cell 51 38906115
2021 SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A. eLife 42 33949310
2022 Piperlongumine synergistically enhances the antitumour activity of sorafenib by mediating ROS-AMPK activation and targeting CPSF7 in liver cancer. Pharmacological research 31 35202819
2019 CPSF7 regulates liver cancer growth and metastasis by facilitating WWP2-FL and targeting the WWP2/PTEN/AKT signaling pathway. Biochimica et biophysica acta. Molecular cell research 27 31837982
2020 Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation. JCI insight 24 31935199
2018 Interactome Analysis of NS1 Protein Encoded by Influenza A H7N9 Virus Reveals an Inhibitory Role of NS1 in Host mRNA Maturation. Journal of proteome research 24 29558158
2023 Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection. Scientific reports 23 37414787
2020 SP1 induced long non-coding RNA LINC00958 overexpression facilitate cell proliferation, migration and invasion in lung adenocarcinoma via mediating miR-625-5p/CPSF7 axis. Cancer cell international 22 31997940
2005 Entamoeba histolytica: comparative genomics of the pre-mRNA 3' end processing machinery. Experimental parasitology 20 15955310
2019 Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis. Journal of cellular physiology 16 30815864
2023 miR-624 accelerates the growth of liver cancer cells by inhibiting EMC3. Non-coding RNA research 12 37810370
2022 Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade. Nucleic acids research 12 35993810
2012 Knockdown of pre-mRNA cleavage factor Im 25 kDa promotes neurite outgrowth. Biochemical and biophysical research communications 11 22898046
2022 CFIm-mediated alternative polyadenylation safeguards the development of mammalian pre-implantation embryos. Stem cell reports 9 36563685
2018 Effect of CFIm25 knockout on RNA polymerase II transcription. BMC research notes 9 30547832
2023 Revised iCLIP-seq Protocol for Profiling RNA-protein Interaction Sites at Individual Nucleotide Resolution in Living Cells. Bio-protocol 6 37323634
2020 Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier. Genes 4 32486318
2022 Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway. Open medicine (Warsaw, Poland) 2 36349192
2026 SNRPD2-CPSF7-UBE2K axis drives ovarian cancer progression via alternative splicing-polyadenylation crosstalk. Oncogene 0 42098443

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