Affinage

INTS15

Integrator complex subunit 15 · UniProt Q96N11

Length
449 aa
Mass
50.0 kDa
Annotated
2026-04-28
6 papers in source corpus 4 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTS15 is a subunit of the Integrator complex that functions in RNA polymerase II transcription termination, snRNA 3ʹ-end processing, and cell cycle control. It assembles with INTS10, INTS13, and INTS14 into a scorpion-tail-shaped module that, in cryo-EM structures of the Integrator–PP2A complex, contacts the DSIF DNA clamp to facilitate Pol II termination (PMID:38570683, PMID:36920904). INTS15 supports snRNA 3ʹ-end maturation, and its depletion causes widespread mRNA missplicing and impaired RNA Pol II pause regulation at a subset of genes (PMID:36851842, PMID:36920904). Overexpression of INTS15 activates p53/p21 to induce G1 arrest, whereas its knockdown disrupts G2/M progression and promotes apoptosis, and it is required for axonal outgrowth in human iPSC-derived retinal ganglion cells (PMID:40194948, PMID:36851842).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2023 Medium

    Establishing that INTS15 is a previously unrecognized Integrator subunit resolved how the INTS10/13/14 module interfaces with the rest of the complex, particularly the PP2A module.

    Evidence Mass spectrometry proteomics and AlphaFold2 structural prediction in human cells

    PMID:36920904

    Open questions at the time
    • Interaction topology relied on AlphaFold2 prediction without experimental atomic-resolution confirmation at the time
    • Stoichiometry of INTS15 within the complex was not determined
    • No reconstitution of a minimal INTS15-containing subcomplex was performed
  2. 2023 High

    Demonstrating that INTS15 perturbation alters Pol II pausing and causes snRNA 3ʹ-end processing defects and widespread missplicing established its functional contribution to Integrator-mediated transcriptional and RNA processing activities.

    Evidence CRISPRi/knockdown with genomic occupancy readouts, snRNA processing assays, and RNA-seq splicing analysis in human cells

    PMID:36851842 PMID:36920904

    Open questions at the time
    • Whether INTS15 directly contacts nascent RNA or acts solely through structural scaffolding is unknown
    • Gene-level specificity of pausing effects not fully defined
  3. 2023 Medium

    Showing that INTS15 loss impairs axonal outgrowth in iPSC-derived retinal ganglion cells linked its molecular functions to a neurodevelopmental cellular phenotype.

    Evidence siRNA knockdown in human iPSC-derived neural progenitors with morphometric axon readouts

    PMID:36851842

    Open questions at the time
    • Mechanism connecting snRNA/splicing defects to axon growth was not dissected
    • In vivo validation in animal models is lacking
  4. 2024 High

    High-resolution cryo-EM structures of the full Integrator–PP2A complex in multiple functional states revealed that INTS15/10/13/14 forms a scorpion-tail module whose tip contacts the DSIF DNA clamp, providing a structural mechanism for Pol II termination.

    Evidence Cryo-EM of Integrator–PP2A in pre-termination, post-termination, and free states

    PMID:38570683

    Open questions at the time
    • Functional mutagenesis of the INTS15 'sting' contact with DSIF has not been performed
    • Whether the clamp-opening mechanism is universal or context-specific is unresolved
  5. 2025 Medium

    Gain- and loss-of-function experiments showed INTS15 controls cell cycle progression via the p53/p21 axis and is required for G2/M transition, expanding its role beyond RNA processing to proliferation and differentiation control.

    Evidence Cumate-inducible overexpression and siRNA knockdown in HeLa and iPSCs with cell cycle, apoptosis, and differentiation readouts

    PMID:40194948

    Open questions at the time
    • Whether cell cycle effects are direct or secondary to global splicing/transcription defects is not resolved
    • The transcriptional targets through which INTS15 activates p53/p21 are not identified
    • Single-lab observation awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct molecular contacts between INTS15 and DSIF/Pol II that drive clamp opening, and the causal chain linking INTS15-dependent RNA processing to cell cycle and differentiation phenotypes, remain to be established.
  • No mutagenesis or reconstitution study has isolated INTS15's specific structural contribution to termination
  • No separation-of-function alleles distinguish RNA processing versus cell cycle roles
  • No animal model phenotype has been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005654 nucleoplasm 2
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 was identified as an additional subunit of the Integrator complex, assembling primarily with the INTS13/14/10 module and interfacing with the Integrator-PP2A module, as determined by proteomics and AlphaFold2-based structural prediction. Proteomics (mass spectrometry) and machine-learning structure prediction (AlphaFold2) Cell reports Medium 36920904
2023 INTS15 modulates RNA polymerase II pausing at a subset of genes, as revealed by functional genomics analysis following its perturbation. Functional genomics (CRISPRi/knockdown with genomic occupancy readouts) Cell reports Medium 36920904
2023 INTS15 stably interacts with the Integrator complex to support small nuclear RNA (snRNA) 3' end processing, and its knockdown causes missplicing of a large number of genes. Co-immunoprecipitation/stable interaction assay, knockdown with RNA-seq splicing analysis, and snRNA 3' end processing assay Human molecular genetics High 36851842
2023 INTS15 is critical for axonal outgrowth in retinal ganglion cells derived from human iPS cells, as demonstrated by INTS15 knockdown causing defects in this process. INTS15 knockdown in human iPS cell-derived neural progenitor cells with axonal outgrowth phenotypic readout Human molecular genetics Medium 36851842
2024 Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS15, together with INTS10, INTS13, and INTS14, forms a scorpion-tail-shaped module; the 'sting' of this module may open the DSIF DNA clamp to facilitate Pol II termination. Cryo-electron microscopy (cryo-EM) structural determination of the Integrator-PP2A complex in pre-termination, post-termination, and free states Nature High 38570683
2025 INTS15 overexpression activates p53 and p21 expression to induce G1 cell cycle arrest, while INTS15 knockdown causes defects in G2/M progression and apoptosis in HeLa and human iPS cells. Cumate-inducible INTS15 overexpression and siRNA knockdown in HeLa and iPS cells with cell cycle analysis and apoptosis readouts 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. INTS15 overexpression in human iPS cells with in vitro differentiation assays measuring germ layer and retinal tissue formation Genes to cells : devoted to molecular & cellular mechanisms Medium 40194948

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 425 35688146
2024 Structural basis of Integrator-dependent RNA polymerase II termination. Nature 49 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