SRSF7

SRSF7 is an SR-family RNA-binding protein that governs RNA processing across splicing, 3′-end formation, miRNA biogenesis, and nuclear export, with downstream consequences for cell proliferation, senescence, metabolism, and DNA repair (PMID:32123389, PMID:33706811). It maintains its own protein homeostasis through a negative-feedback circuit in which SRSF7 binding to its own pre-mRNA promotes inclusion of a poison cassette exon and NMD-coupled degradation; at elevated levels, intronic SRSF7 binding and oligomerization drive assembly of large nuclear bodies that sequester SRSF7 transcripts at their transcription site to restore normal protein levels (PMID:32123389). In 3′-end processing, SRSF7 binds upstream of proximal polyadenylation sites and recruits the cleavage factor FIP1 to favor short 3′UTRs, a function dependent on domains unique to SRSF7 and independent of splicing (PMID:33706811). As a splicing regulator it controls specific targets with defined cellular outputs: Fas splicing linked to proliferation and apoptosis (PMID:29556298), MDM2 splicing generating the MDM2-C variant that stabilizes p53 to drive senescence (PMID:38159247), PKM isoform choice that produces a pro-fibrotic metabolic shift in fibroblasts (PMID:40654335), and ATM splicing that enhances DNA damage repair (PMID:40840404). SRSF7 also stimulates Microprocessor cleavage of pri-miRNAs through CNNC/CRC motifs (PMID:36750366) and, with SRSF1, bridges intronless RNAs such as NKILA to the TREX components UAP56 and ALYREF for nuclear export (PMID:34096602). Its activity is regulated post-translationally by CLK1-mediated phosphorylation at serine 231 (PMID:40840404) and by piRNA binding to its RRM domain that blocks its ubiquitination and degradation (PMID:42217722).

1. 2018 Medium

   Establishing SRSF7 as a functionally relevant splicing regulator in cancer, the first finding tied its activity to a defined splicing target and cellular phenotype.

   Evidence siRNA knockdown and stable cell lines with RT-PCR for Fas splice variants, MTS and flow cytometry in colon and lung cancer cells

   PMID:29556298

   Open questions at the time

   • Splicing mechanism on Fas not dissected at the RNA level
   • No direct binding map to the Fas pre-mRNA
2. 2020 High

   Resolved how SRSF7 controls its own abundance, revealing an autoregulatory NMD-plus-nuclear-body circuit rather than simple feedback transcription.

   Evidence iCLIP, NMD reporter assays, live-cell imaging of nuclear body assembly and binding-site mutagenesis in murine P19 cells

   PMID:32123389

   Open questions at the time

   • Structural basis of SRSF7 oligomerization unresolved
   • Whether the Split-ORF dominant-negative isoform exists at endogenous levels in other cell types unknown
3. 2020 Medium

   Connected SRSF7 to developmental timing by showing it drives age-dependent splice-isoform switches controlling anabolism and growth.

   Evidence Postnatal RNA-seq across multiple tissues with in vivo knockdown and RT-PCR validation of Eif4a2 and Rbm7

   PMID:32146325

   Open questions at the time

   • Direct binding of SRSF7 to the affected pre-mRNAs not shown
   • Mechanism timing the switch unknown
4. 2021 High

   Defined a splicing-independent role in 3′-end formation, showing SRSF7 sets 3′UTR length by recruiting a polyadenylation factor.

   Evidence iCLIP, 3′-end sequencing, domain deletion/swap experiments and FIP1 co-immunoprecipitation

   PMID:33706811

   Open questions at the time

   • Structural detail of the SRSF7–FIP1 interface not defined
   • Concentration dependence in vivo across tissues not mapped
5. 2021 High

   Extended SRSF7 function to nuclear export of intronless RNAs by linking sequence-specific binding to the TREX/TAP machinery.

   Evidence In vitro RNP purification, mass spectrometry, reciprocal RNA/protein IP and CAR-N deletion knock-in for NKILA

   PMID:34096602

   Open questions at the time

   • Generality across other intronless transcripts not established
   • Relative contributions of SRSF7 versus SRSF1 not separated
6. 2021 Medium

   Implicated SRSF7 in miRNA biogenesis, showing it stimulates Microprocessor cleavage via defined RNA motifs.

   Evidence High-throughput in vitro pri-miRNA cleavage assays with motif/structure mutagenesis and cellular cleavage-site mapping

   PMID:36750366

   Open questions at the time

   • Set of physiologically regulated miRNAs unknown
   • Whether SRSF7 directly contacts Microprocessor components not shown
7. 2023 Medium

   Linked SRSF7 loss to senescence through an MDM2 splice variant that stabilizes p53, defining a tumor-suppressive splicing axis.

   Evidence RNA-seq of senescent cells, siRNA knockdown in fibroblasts, RT-PCR for MDM2 variants and MDM2-C overexpression rescue

   PMID:38159247

   Open questions at the time

   • Direct SRSF7 binding on MDM2 pre-mRNA not mapped
   • Whether other p53-pathway splice events contribute unknown
8. 2023 Medium

   Revealed a non-canonical chromatin role for SRSF7, acting at a promoter with a histone methyltransferase to activate transcription.

   Evidence Macrophage genetics, ChIP for STAT1 and Pol II, and co-immunoprecipitation of SRSF7 with KMT5a (preprint)

   PMID:37503164

   Open questions at the time

   • Preprint not peer-reviewed
   • Whether the chromatin role generalizes beyond the Irf7 locus unknown
9. 2024 Medium

   Identified SRSF7 as a host restriction factor for influenza polymerase, with a species-specific determinant region.

   Evidence siRNA knockdown, domain deletion mapping (aa 206–228), polymerase reporter assays and lysosome/proteasome inhibitor experiments

   PMID:39134172

   Open questions at the time

   • Molecular mechanism of polymerase inhibition unresolved
   • How PB2-627K triggers lysosomal SRSF7 degradation not defined
10. 2025 Medium

    Connected CLK1 phosphorylation of SRSF7 at S231 to ATM splicing and chemoresistance, providing a regulated-input-to-output axis.

    Evidence LC-MS of a circRNA-associated RBP, phospho-site mutagenesis, ATM203 RT-PCR and patient-derived organoid/xenograft validation in PDAC

    PMID:40840404

    Open questions at the time

    • Whether S231 phosphorylation broadly tunes other SRSF7 targets unknown
    • Direct kinetics of CLK1–SRSF7 phosphorylation not measured
11. 2025 Medium

    Established SRSF7 as a driver of pro-fibrotic metabolic reprogramming via PKM splicing in vivo.

    Evidence Fibroblast-specific conditional knockout mice, bleomycin model, RNA-seq, PKM RT-PCR and metabolic assays with human IPF fibroblasts

    PMID:40654335

    Open questions at the time

    • Direct SRSF7 binding on PKM pre-mRNA not mapped here
    • Relationship to canonical PKM splicing regulators not resolved
12. 2025 Medium

    Showed SRSF7 protein stability is controlled by a piRNA that binds its RRM and blocks ubiquitination, coupling SRSF7 levels to PKM splicing in cardiac fibrosis.

    Evidence RNA pulldown with RRM domain mapping, ubiquitination assays, AAV-mediated myofibroblast KD/OE in mice and metabolic assays

    PMID:42217722

    Open questions at the time

    • Ubiquitin ligase acting on SRSF7 not identified
    • Whether piRNA control of SRSF7 operates outside cardiac fibroblasts unknown
13. 2025 Medium

    Linked SRSF7 to neuronal axon regeneration via STMN2 abundance, with disease relevance to C9ORF72 dipeptide toxicity.

    Evidence siRNA knockdown in iPSC-derived neurons, global phospho-proteomics, axonal regeneration assays and STMN2 rescue

    PMID:40140908

    Open questions at the time

    • Whether SRSF7 controls STMN2 through splicing or another mechanism not defined
    • Functional consequence of poly-PR-altered SRSF7 phosphorylation not established

• How SRSF7's diverse activities — autoregulation, 3′-end choice, splicing, export, miRNA processing, and chromatin action — are coordinately deployed across cell types and integrated with its phosphorylation and stability inputs remains unresolved.
• No unified model linking SRSF7 concentration, modification, and target selection
• Genome-wide rules for proximal-PAS versus splicing versus export decisions undefined