Affinage

CPSF7

Cleavage and polyadenylation specificity factor subunit 7 · UniProt Q8N684

Round 2 corrected
Length
471 aa
Mass
52.0 kDa
Annotated
2026-04-28
54 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CPSF7 (CFIm59) is a large subunit of the cleavage factor Im (CFIm) complex that regulates mRNA 3′ end processing and alternative polyadenylation (APA), thereby controlling 3′ UTR length across the transcriptome. Within the CFIm heterotetramer, CPSF7 activates enhancer-containing poly(A) sites through its arginine-serine (RS) domain, which binds the Fip1 subunit of CPSF in a phosphorylation-regulated manner; genome-wide loss-of-function studies reveal that CPSF7 and its paralog CFIm68 exert distinct and sometimes opposing effects on poly(A) site selection (PMID:29276085, PMID:35993810). Beyond canonical polyadenylation, the RS domain of CPSF7 participates in CFIm-mediated promotion of MAT2A detained intron splicing, linking the complex to S-adenosylmethionine homeostasis (PMID:33949310). CPSF7-dependent APA of specific transcripts such as WWP2 and PTEN connects its RNA-processing activity to PI3K/AKT signaling output in liver and lung cancer cells (PMID:31837982, PMID:35993810).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2010 High

    Establishing that CPSF7 is a stable subunit of the CFIm heterotetramer resolved the composition of the complex responsible for APA regulation and showed that CFIm59 and CFIm68 are structurally related, partially redundant large subunits.

    Evidence Reciprocal co-immunoprecipitation and biochemical fractionation from HeLa cells

    PMID:20695905

    Open questions at the time
    • No crystal structure of CFIm59-containing complex
    • Relative stoichiometry of CFIm59 vs CFIm68 in endogenous complexes not quantified
  2. 2012 High

    Genome-wide APA profiling after individual subunit knockdowns demonstrated that CFIm controls 3′ UTR length transcriptome-wide, but CFIm59 loss alone does not phenocopy CFIm25 or CFIm68 loss, establishing a non-redundant functional hierarchy among subunits.

    Evidence siRNA knockdown of individual CFIm subunits followed by high-throughput poly(A) site sequencing in HEK293 cells

    PMID:23187700

    Open questions at the time
    • Molecular basis for CFIm59's distinct contribution versus CFIm68 unknown
    • Whether CFIm59 has targets independent of the CFIm complex not addressed
  3. 2016 Medium

    Demonstrating that CPSF7 is recruited to HIV-1 preintegration complexes via CPSF6-capsid interaction placed the CFIm complex in a viral biology context, while showing that CPSF7 is dispensable for HIV-1 integration targeting.

    Evidence Co-immunoprecipitation and virological assays with CPSF6 mutants defective in CFIm assembly

    PMID:26994143

    Open questions at the time
    • Whether CPSF7 recruitment alters HIV-1 gene expression or RNA processing not tested
    • Direct CPSF7–capsid binding not demonstrated
  4. 2017 High

    Identification of the RS domain–Fip1 interaction as the mechanism by which CFIm59 activates enhancer-dependent poly(A) sites explained how APA is regulated and revealed phosphorylation as a toggle for this activity.

    Evidence CLIP-seq, in vitro binding assays, RS domain mutagenesis, phosphorylation modulation, and global APA sequencing

    PMID:29276085

    Open questions at the time
    • Kinase(s) responsible for RS domain hyper-phosphorylation not identified
    • Structural details of RS–Fip1 interface unresolved
  5. 2019 Medium

    Linking CPSF7-dependent APA of WWP2 to PTEN ubiquitination and AKT signaling in liver cancer established a specific oncogenic downstream consequence of CPSF7's RNA-processing activity.

    Evidence siRNA knockdown and overexpression with isoform analysis of WWP2, proliferation/migration assays, and PTEN/AKT pathway Western blotting in liver cancer cells

    PMID:31837982

    Open questions at the time
    • Direct biochemical reconstitution of CPSF7-dependent WWP2 APA not performed
    • In vivo tumor model validation absent
  6. 2021 High

    Discovery that CFIm59's RS domain promotes MAT2A detained intron splicing revealed a non-canonical, polyadenylation-independent function for the CFIm complex in SAM metabolism.

    Evidence CRISPR knockout screen, siRNA knockdown, RT-PCR intron retention analysis, SAM metabolite measurement, and RS domain deletion mutagenesis

    PMID:33949310

    Open questions at the time
    • Mechanism by which RS domain facilitates intron splicing (e.g., spliceosome recruitment) not elucidated
    • Scope of CFIm-dependent splicing beyond MAT2A not defined
  7. 2022 High

    Genome-wide comparison of CFIm59 versus CFIm68 loss-of-function showed they have opposing effects on APA of specific transcripts including PTEN, resolving the long-standing question of subunit-specific roles within the CFIm complex.

    Evidence Deep 3′ end sequencing in KO and KD cell lines for CFIm59 and CFIm68 with differential APA analysis

    PMID:35993810

    Open questions at the time
    • Structural or biochemical basis for opposing APA effects not identified
    • Whether opposing regulation is context- or cell-type-dependent not tested
  8. 2023 Medium

    Exclusion of CPSF7 from HIV-1-induced CPSF6/CPSF5 biomolecular condensates in the nucleus further delineated its distinct role within the CFIm complex, separating canonical mRNA processing from the HIV nuclear import pathway.

    Evidence Live-cell fluorescence imaging with condensate disruption assays and HIV-1 capsid mutants in T cells and macrophages

    PMID:37414787

    Open questions at the time
    • Functional consequence of CPSF7 exclusion from condensates on mRNA processing not assessed
    • Whether CPSF7 forms separate condensates not investigated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The kinase(s) that regulate RS domain phosphorylation of CPSF7, the structural basis for its opposing APA function relative to CFIm68, and the full scope of its non-canonical splicing targets remain unresolved.
  • No kinase identified for RS domain phosphorylation
  • No high-resolution structure of CFIm59-containing CFIm complex
  • Genome-wide catalog of CFIm59-dependent splicing events lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 2
Localization
GO:0005654 nucleoplasm 3
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-162582 Signal Transduction 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CPSF6FIP1L1NUDT21WWP2
Complex memberships
CFIm (Cleavage Factor Im)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 CFIm (cleavage factor Im) forms stable heterotetramers through dimerization of the CFIm25 subunit, and the complex per se is responsible for controlling alternative polyadenylation. CFIm68 (CPSF7 paralog) and CFIm59 (CPSF7) are structurally related and functionally redundant for APA regulation, though CFIm68 appears to have higher specific activity. Knockdown of CFIm25 causes an upstream shift in poly(A) site utilization. Immunoprecipitation, knockdown experiments, biochemical fractionation from HeLa cells Genes to cells High 20695905
2012 Loss-of-function of CFIm68 and CFIm25 (but not CFIm59/CPSF7 alone) leads to transcriptome-wide increase in use of proximal polyadenylation sites in HEK293 cells, establishing that CFIm subunits generally control 3' UTR length, with CFIm59 (CPSF7) playing a distinct, non-redundant role compared to CFIm68 in global APA. High-throughput sequencing of polyadenylation sites after siRNA knockdown of individual CFIm subunits in HEK293 cells RNA biology High 23187700
2012 Knockdown of CFIm25 in neuronal cells increases primary dendrite number and promotes NGF-induced neurite extension in PC12 cells, placing the CFIm complex (which includes CFIm59/CPSF7 as a large subunit) upstream of NGF-induced RhoA inactivation in neuritogenesis. siRNA knockdown of CFIm25 in hippocampal neurons and PC12 cells; morphological assays; dominant-negative and constitutively active RhoA epistasis experiments Biochemical and biophysical research communications Medium 22898046
2017 CFIm functions as an enhancer-dependent activator of mRNA 3' processing by binding and activating enhancer-containing poly(A) sites. The activation function of CFIm59 (CPSF7) and CFIm68 is mediated by their arginine-serine repeat (RS) domains, which bind specifically to an RS-like region in the CPSF subunit Fip1. This interaction is inhibited by hyper-phosphorylation of the RS domains of CFIm68/59. CLIP-seq, in vitro binding assays, mutagenesis of RS domains, phosphorylation inhibition/induction experiments, global APA sequencing Molecular cell High 29276085
2016 CPSF7 (CFIm59), together with CPSF5 (CFIm25) and CPSF6 (CFIm68), is a subunit of the CFIm complex that is recruited to HIV-1 preintegration complexes in a CPSF6-dependent manner via capsid binding. CPSF5 and CPSF7 appear to facilitate CPSF6 binding to HIV-1 capsid, but are not required for the role of CPSF6 in directing preferential HIV-1 integration into active genes. Co-immunoprecipitation, virological assays, integration site sequencing, CPSF6 variant with mutations blocking CFIm assembly The Journal of biological chemistry Medium 26994143
2018 CPSF7 interacts with influenza A H7N9 virus NS1 protein in human cells; this interaction was confirmed by co-immunoprecipitation. Overexpression of H7N9 NS1 and H7N9 virus infection interfere with pre-mRNA polyadenylation in host cells, implicating CPSF7 as a target through which NS1 inhibits host mRNA maturation. GeLC-MS/MS interactome, co-immunoprecipitation, immunoblotting, polyadenylation assay after NS1 overexpression or viral infection Journal of proteome research Medium 29558158
2019 CPSF7 (CFIm59) regulates liver cancer growth and metastasis by facilitating production of the full-length WWP2-FL isoform through its role in alternative mRNA processing. WWP2-FL promotes PTEN ubiquitination, thereby activating AKT signaling. CPSF7 knockdown suppresses cell proliferation, migration, and colony formation by inhibiting PTEN/AKT signaling. siRNA knockdown, overexpression, cell proliferation/migration/colony formation assays, Western blotting for PTEN/AKT pathway, isoform analysis for WWP2 Biochimica et biophysica acta. Molecular cell research Medium 31837982
2020 Stiff matrix downregulates expression of CFIm59 (CPSF7), CFIm68, and CFIm25 subunits and promotes alternative polyadenylation favoring proximal poly(A) sites in COL1A1 and FN1 in primary human lung fibroblasts. Knockdown of CFIm59 individually is not sufficient to drive stiff matrix-induced APA of COL1A1; CFIm68 and CFIm25 are indispensable for this response, distinguishing the functional contributions of CFIm59/CPSF7 from other subunits. Hydrogel-based mechanical stimulation model, siRNA knockdown and overexpression of individual CFIm subunits, 3' end sequencing (APA analysis), bleomycin mouse model of pulmonary fibrosis JCI insight Medium 31935199
2021 CFIm59 (CPSF7) and CFIm68 RS domains are required for CFIm-mediated promotion of MAT2A detained intron splicing. CFIm25 (NUDT21) promotes MAT2A splicing and SAM homeostasis independent of poly(A) site selection, revealing a non-canonical splicing role for the CFIm complex (including CPSF7) in regulating SAM metabolism. CRISPR knockout screen, siRNA knockdown, RT-PCR for intron retention, SAM metabolite measurement, domain deletion/mutation analysis of RS domains eLife High 33949310
2022 CFIm59 (CPSF7) and CFIm68 have distinct, opposing functions in regulating alternative polyadenylation of Pten mRNA: their differential activity has widespread impact on APA across transcriptomes, including numerous factors in the PI3K/AKT signaling pathway that PTEN counter-regulates. Deep sequencing of 3' ends in KO and KD cell lines for CFIm59 and CFIm68, differential APA analysis, cancer genomics analysis of PTEN-driven cancers Nucleic acids research High 35993810
2022 CPSF7 silencing in lung adenocarcinoma cells inhibits cell viability, colony formation, migration, and invasion by blocking the AKT/mTOR signaling pathway. Activation of AKT/mTOR with SC79 rescues the antitumor effects of CPSF7 silencing, placing CPSF7 upstream of AKT/mTOR in lung cancer cell biology. siRNA knockdown and overexpression in A549 cells, CCK-8 and colony formation assays, wound healing and Transwell assays, Western blotting for AKT/mTOR pathway proteins, SC79 rescue experiment Open medicine Low 36349192
2022 CPSF7 knockdown promotes growth inhibition by sorafenib or piperlongumine in liver cancer cells, while CPSF7 overexpression alleviates sorafenib cytotoxicity. Piperlongumine disrupts RNA processing and decreases CPSF7 expression in a time- and concentration-dependent manner. Mechanistically, this connects CPSF7 to ROS-AMPK activation and drug sensitivity. RNA-sequencing, flow cytometry, CCK-8 assay, siRNA knockdown and overexpression, xenograft mouse model, Western blotting for AMPK pathway Pharmacological research Medium 35202819
2023 Upon HIV-1 entry into the nucleus, CPSF6 and CPSF5 (but not CPSF7) co-localize in biomolecular condensates (puncta-like structures) that are important for productive HIV-1 infection. CPSF7 does not participate in these HIV-1-induced CPSF6/CPSF5 condensates, indicating that CPSF7's role in the CFIm complex is distinct from the HIV-1-relevant functions of CPSF6/CPSF5. Live-cell fluorescence imaging, osmotic stress/hexanediol condensate disruption assays, HIV-1 infection with capsid mutants (N74D, A77V), co-localization analysis in T cells and macrophages Scientific reports Medium 37414787
2023 CPSF7 binds RNA at specific sites in living cells, as determined by iCLIP-seq. CPSF7 was used as a bait protein in the iCLIP-1.5 protocol, establishing it as an RNA-binding protein that can be crosslinked to target RNAs for nucleotide-resolution binding site mapping. iCLIP-seq (UV crosslinking and immunoprecipitation followed by high-throughput sequencing) on CPSF7 protein Bio-protocol Low 37323634
2020 LINC00958 acts as a competing endogenous RNA (ceRNA) to sponge miR-625-5p, which directly targets CPSF7 and downregulates its expression. Loss of LINC00958 or overexpression of miR-625-5p reduces CPSF7 levels and inhibits lung adenocarcinoma cell proliferation, migration, and invasion, placing CPSF7 downstream of the LINC00958/miR-625-5p axis. Luciferase reporter assay, RNA pull-down, RIP assay, siRNA/miRNA overexpression, EdU/colony formation/Transwell assays Cancer cell international Medium 31997940

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2002 Comprehensive proteomic analysis of the human spliceosome. Nature 725 12226669
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2013 Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell reports 307 23403292
2017 A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Molecular cell 248 28431233
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2017 Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation. Molecular cell 176 29276085
2012 Cleavage factor Im is a key regulator of 3' UTR length. RNA biology 130 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 101 23939832
2010 Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation. Genes to cells : devoted to molecular & cellular mechanisms 66 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 48 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 30 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 25 31837982
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 22 37414787
2020 Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation. JCI insight 22 31935199
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 The Arabidopsis pre-mRNA 3' end processing related protein FIP1 promotes seed dormancy via the DOG1 and ABA pathways. The Plant journal : for cell and molecular biology 13 37035898
2023 miR-624 accelerates the growth of liver cancer cells by inhibiting EMC3. Non-coding RNA research 12 37810370
2012 Knockdown of pre-mRNA cleavage factor Im 25 kDa promotes neurite outgrowth. Biochemical and biophysical research communications 11 22898046
2022 Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade. Nucleic acids research 10 35993810
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 4 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) 1 36349192