Affinage

INTS15

Integrator complex subunit 15 · UniProt Q96N11

Length
449 aa
Mass
50.0 kDa
Annotated
2026-06-10
6 papers in source corpus 4 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTS15 (C7orf26) is a bona fide subunit of the Integrator complex that supports RNA polymerase II transcriptional regulation and snRNA 3' end processing (PMID:36920904, PMID:36851842). It assembles primarily with the INTS13/INTS14/INTS10 module and interfaces with the Integrator-associated PP2A module (PMID:36920904); cryo-EM of the complete Integrator-PP2A complex resolves these four subunits as a scorpion-tail-shaped 'sting' module positioned to open the DSIF DNA clamp and facilitate promoter-proximal RNAPII termination (PMID:38570683). Consistent with this structural placement, INTS15 modulates RNAPII pausing at a subset of genes and is required for snRNA 3' end processing, with its loss causing widespread missplicing as a secondary consequence and disrupting genes linked to eye and brain development (PMID:36851842, PMID:36920904). INTS15 also couples to cell cycle control: overexpression activates p53 and p21 to enforce G1 arrest, while knockdown produces G2/M defects and apoptosis (PMID:40194948). Functionally, INTS15 is critical for differentiation programs, including retinal ganglion cell axonal outgrowth and retinal tissue formation (PMID:40194948, PMID:36851842).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2023 Medium

    Establishing that the previously uncharacterized C7orf26 is itself an Integrator subunit defined INTS15 as part of the transcription machinery rather than an isolated factor.

    Evidence Proteomics and AlphaFold2 structure prediction with functional genomics placing INTS15 in the INTS13/14/10 module and interfacing with Int-PP2A

    PMID:36920904

    Open questions at the time
    • Module assignment rested on prediction plus proteomics without an experimental structure
    • Stoichiometry and assembly order within the module not resolved
  2. 2023 Medium

    Linking INTS15 loss to snRNA 3' end processing defects and downstream missplicing connected the subunit to a concrete biochemical output of the complex and to developmental gene programs.

    Evidence Ints15 KO/mutant mice, siRNA knockdown, iPSC-derived neural progenitors, RNA-seq splicing analysis, and co-immunoprecipitation

    PMID:36851842

    Open questions at the time
    • Missplicing inferred as a secondary consequence rather than a direct INTS15 activity
    • No independent replication of the interaction and processing roles
  3. 2023 Medium

    Showing INTS15 modulates RNAPII pausing at a subset of genes extended its role beyond snRNA processing to broader transcriptional regulation.

    Evidence Functional genomics readout of RNAPII pausing after INTS15 perturbation

    PMID:36920904

    Open questions at the time
    • Gene selectivity of the pausing effect not mechanistically explained
    • Single-lab functional genomics without orthogonal validation
  4. 2024 High

    Cryo-EM resolved how INTS15 contributes structurally, placing it in a scorpion-tail module poised to open the DSIF DNA clamp during promoter-proximal termination.

    Evidence Cryo-EM of the complete Integrator-PP2A complex in pre-termination, post-termination, and free states

    PMID:38570683

    Open questions at the time
    • DSIF clamp-opening function is a structural proposal not yet tested by mutation
    • Specific residues of INTS15 mediating the activity not defined
  5. 2025 Medium

    Coupling INTS15 dosage to p53/p21 activation and cell cycle phase progression revealed a role in cell cycle control beyond transcription.

    Evidence Cumate-inducible overexpression in HeLa and iPS cells, siRNA knockdown, cell cycle and gene expression analyses

    PMID:40194948

    Open questions at the time
    • Mechanism linking Integrator function to p53/p21 induction not established
    • Whether the effect requires Integrator assembly is untested
  6. 2025 Low

    Demonstrating that INTS15 promotes germ-layer formation and retinal differentiation tied the gene to developmental programs in vitro.

    Evidence iPS cell embryoid body and retinal differentiation assays with inducible INTS15 overexpression

    PMID:40194948

    Open questions at the time
    • Single-lab differentiation assay without independent replication
    • No molecular pathway connecting INTS15 to differentiation outcomes

Open questions

Synthesis pass · forward-looking unresolved questions
  • How INTS15's structural role in termination mechanistically produces its gene-selective pausing, snRNA processing, cell cycle, and developmental phenotypes remains unresolved.
  • No mutational test of the proposed DSIF clamp-opening function
  • Mechanism linking INTS15 to p53/p21 and developmental programs unknown
  • No disease-causative variant established in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1640170 Cell Cycle 1 R-HSA-8953854 Metabolism of RNA 1
Partners
INTS10INTS13INTS14
Complex memberships
Integrator complexIntegrator-PP2A complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 INTS15 (C7orf26) is an additional subunit of the Integrator complex, assembling primarily with the INTS13/14/10 module and interfacing with the Int-PP2A module, as determined by proteomics and AlphaFold2-based structural prediction. Proteomics (mass spectrometry), AlphaFold2 machine-learning structure prediction, functional genomics Cell reports Medium 36920904
2023 INTS15 knockdown causes missplicing of a large number of genes, probably as a secondary consequence of disrupted snRNA 3' end processing, and substantially affects genes associated with eye and brain development; INTS15 stably interacts with the Integrator complex to support small nuclear RNA 3' end processing. Ints15 knockout/mutant mouse models, siRNA knockdown, iPS cell-derived neural progenitor cells, RNA-seq/splicing analysis, co-immunoprecipitation Human molecular genetics Medium 36851842
2023 INTS15 modulates RNA polymerase II pausing at a subset of genes, as revealed by functional genomics analysis following perturbation of INTS15. Functional genomics (ChIP-seq/PRO-seq or equivalent RNAPII pausing analysis) Cell reports Medium 36920904
2024 Cryo-EM structures of the complete Integrator-PP2A complex reveal a scorpion-tail-shaped INTS10-INTS13-INTS14-INTS15 module (the 'sting') that may open the DSIF DNA clamp to facilitate RNA polymerase II termination in the promoter-proximal region. Cryo-electron microscopy (cryo-EM) of Integrator-PP2A complex in pre-termination, post-termination, and free states Nature High 38570683
2025 Overexpression of INTS15 activates p53 and p21 expression to induce G1 arrest, while INTS15 knockdown results in defects in G2/M progression and apoptosis; INTS15 expression levels vary by cell type and fluctuate during the cell cycle. Cumate-inducible overexpression in HeLa and human iPS cells, siRNA knockdown, cell cycle analysis, gene expression assays Genes to cells : devoted to molecular & cellular mechanisms Medium 40194948
2025 INTS15 promotes formation of the three germ layers and differentiation into late retinal tissues in iPS cell in vitro differentiation assays. Human iPS cell differentiation (embryoid body and retinal differentiation assays) with cumate-inducible INTS15 overexpression Genes to cells : devoted to molecular & cellular mechanisms Low 40194948
2023 INTS15 is critical for axonal outgrowth in retinal ganglion cells derived from human iPS cells, as shown by INTS15 knockdown experiments. siRNA knockdown in human iPS cell-derived retinal ganglion cells, axonal outgrowth assay Human molecular genetics Low 36851842

Source papers

Stage 0 corpus · 6 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq. Cell 454 35688146
2024 Structural basis of Integrator-dependent RNA polymerase II termination. Nature 53 38570683
2023 A combinatorial approach to uncover an additional Integrator subunit. Cell reports 29 36920904
2023 Integrator complex subunit 15 controls mRNA splicing and is critical for eye development. Human molecular genetics 10 36851842
2024 Exploring the molecular mechanisms of asthma across multiple datasets. Annals of medicine 3 38489401
2025 INTS15, A Subunit of the Integrator Complex, Plays a Key Regulatory Role in Cell Cycle and Differentiation. Genes to cells : devoted to molecular & cellular mechanisms 0 40194948

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