Affinage

INTS12

Integrator complex subunit 12 · UniProt Q96CB8

Length
462 aa
Mass
48.8 kDa
Annotated
2026-06-10
12 papers in source corpus 5 papers cited in narrative 5 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

INTS12 is a subunit of the Integrator complex that contributes to snRNA 3' end processing and acts more broadly as a chromatin-associated regulator of RNA Polymerase II transcriptional elongation (PMID:23288851, PMID:28335732). Its integration into the Integrator complex depends on a 45-amino-acid N-terminal microdomain that binds and stabilizes the scaffold subunit INTS1; notably, the conserved PHD finger that defines the protein is dispensable for snRNA 3' end cleavage (PMID:23288851). In human cells INTS12 binds genome-wide, enriched at transcriptionally active regions, and its depletion downregulates protein-synthesis pathway genes and reduces translation, while only minimally perturbing snRNA processing—indicating its dominant role is transcriptional rather than snRNA-restricted in this context (PMID:28335732). Consistent with an elongation-attenuator function, INTS12 occupies the HIV-1 promoter and restrains elongation into the viral gene body, such that its loss increases RNAPII gene-body occupancy and promotes proviral reactivation (PMID:40207620). INTS12 also couples cytoplasmic ribotoxic stress to nuclear transcription-coupled nucleotide excision repair: ribotoxic-stress-activated ZAK kinase phosphorylates INTS12, enhancing its interaction with CSB and recruiting Integrator to lesion-stalled Pol II to drive polymerase clearance, TC-NER, and transcription recovery, with this requirement being lesion-context-dependent (PMID:41748916).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2013 High

    Established which part of INTS12 mediates its function, showing that a short N-terminal microdomain—not the defining PHD finger—drives Integrator assembly and snRNA 3' end processing.

    Evidence RNAi rescue with domain deletion/mutagenesis and snRNA 3' cleavage and binding assays in Drosophila S2 cells

    PMID:23288851

    Open questions at the time
    • Does not define the structural basis of the microdomain–INTS1 interaction
    • PHD finger function, if any, remains unassigned
    • Tested in Drosophila; human snRNA dependence not addressed here
  2. 2017 Medium

    Reframed INTS12's principal cellular role from snRNA processing to genome-wide transcriptional regulation, linking it to protein-synthesis gene expression and translational output.

    Evidence siRNA knockdown with RNAseq, ChIP-seq, and translation assays in human lung cells

    PMID:28335732

    Open questions at the time
    • Direct versus indirect regulation of translation genes not separated
    • Mechanism of elongation control not resolved
    • Single cell-type, single lab
  3. 2025 Medium

    Provided a defined locus-level demonstration of INTS12 as an elongation block, showing it restrains RNAPII progression at the HIV-1 provirus and that its loss promotes reactivation.

    Evidence CRISPR screen, knockout, RNAPII ChIP-seq, viral RNA detection, and ex vivo CD4 T-cell reactivation (with corroborating preprint)

    PMID:39257755 PMID:40207620

    Open questions at the time
    • Molecular mechanism of elongation pausing at the promoter not defined
    • Requirement for other Integrator subunits at HIV not tested
    • Generality across host genes versus HIV-specificity unclear
  4. 2026 High

    Connected INTS12 to a cytoplasm-to-nucleus stress-signaling axis, showing ZAK-mediated phosphorylation directs INTS12–CSB-dependent Integrator recruitment to lesion-stalled Pol II for transcription-coupled repair.

    Evidence Knockout/mutagenesis, co-IP, ChIP, TC-NER and transcription recovery assays, UV sensitivity, and ZAK pathway analysis

    PMID:41748916

    Open questions at the time
    • Phosphosite-level requirement and direct ZAK substrate mapping not fully detailed
    • Structural basis of INTS12–CSB interaction unresolved
    • Why the pathway is dispensable for formaldehyde crosslinks mechanistically unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How INTS12's snRNA-processing, genome-wide elongation-attenuation, and DNA-repair recruitment functions are mechanistically unified within the Integrator complex remains open.
  • No structural model integrating the microdomain, PHD finger, and CSB interaction
  • Unknown whether elongation control and TC-NER recruitment use the same INTS12 surfaces
  • Function of the PHD finger still unassigned

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
CSBINTS1ZAK
Complex memberships
Integrator complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 A small 45-amino acid N-terminal microdomain of Drosophila IntS12 (ortholog of INTS12) is both necessary and nearly sufficient for snRNA 3' end cleavage activity in cells depleted of endogenous IntS12. The conserved plant homeodomain (PHD) finger, the defining structural feature of Ints12, is NOT required for snRNA 3' end formation. Mutations within the microdomain abolish binding to other integrator subunits, and this microdomain is sufficient to interact with and stabilize IntS1, the putative scaffold subunit of the Integrator complex. RNAi rescue assay in Drosophila S2 cells; domain deletion/mutagenesis; reporter snRNA 3' end cleavage assay; co-immunoprecipitation/binding assays The Journal of biological chemistry High 23288851
2017 INTS12 depletion in human lung cells causes only minor alterations in snRNA processing but robustly downregulates protein synthesis pathway genes and decreases protein translation. ChIP-seq demonstrates INTS12 binds throughout the genome, enriched at transcriptionally active regions, defining an INTS12 regulome that includes protein synthesis pathway genes. siRNA knockdown; RNAseq; ChIP-seq; protein translation assay in human lung cells BMC genomics Medium 28335732
2025 INTS12 is present on chromatin at the HIV-1 promoter and acts as a transcriptional elongation block to viral reactivation; INTS12 knockout increases RNAPII occupancy in the HIV-1 gene body and promotes full-length HIV RNA production. This effect is more specific to the HIV-1 provirus than broad latency reversal agents and enhances reactivation in primary CD4 T cells from virally suppressed people living with HIV. CRISPR screen; INTS12 knockout; ChIP-seq (RNAPII occupancy); RT-PCR/viral RNA detection; ex vivo CD4 T cell reactivation assay eLife Medium 40207620
2026 INTS12 links cytoplasmic ribotoxic stress response (RSR) to nuclear transcription-coupled nucleotide excision repair (TC-NER). RSR-activated ZAK kinase phosphorylates INTS12, which enhances INTS12 interaction with CSB (Cockayne syndrome protein B) and promotes recruitment of the Integrator complex to lesion-stalled RNA Polymerase II. This facilitates Pol II clearance from DNA lesions and enables efficient TC-NER and transcription recovery. Disruption of this pathway increases cellular sensitivity to UV-induced damage. This requirement is context-dependent: INTS12-mediated Pol II removal is not required for the response to formaldehyde-induced DNA-protein crosslinks, which use a proteasome-dependent pathway instead. INTS12 knockout/mutagenesis; co-immunoprecipitation (INTS12–CSB interaction); ChIP; TC-NER repair assay; transcription recovery assay; UV sensitivity assay; ZAK kinase signaling pathway analysis Nature structural & molecular biology High 41748916
2025 INTS12 knockout promotes HIV-1 reactivation (CRISPR screen finding replicated in preprint prior to eLife publication); INTS12 occupies chromatin at the HIV promoter, and its loss results in more RNAPII in the HIV gene body, indicating a transcriptional elongation block role for INTS12 at HIV. (Preprint version of the eLife paper; findings replicated in the peer-reviewed publication.) CRISPR screen; INTS12 knockout; ChIP; HIV reactivation assay in primary CD4 T cells bioRxivpreprint Medium 39257755

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Armed Exosomes Deliver Proapoptotic Signals to Tumor Site. Clinical cancer research : an official journal of the American Association for Cancer Research 158 26944067
2016 Orientation-specific RAG activity in chromosomal loop domains contributes to Tcrd V(D)J recombination during T cell development. The Journal of experimental medicine 35 27526713
2013 GSTCD and INTS12 regulation and expression in the human lung. PloS one 35 24058608
2013 Functional analysis of the integrator subunit 12 identifies a microdomain that mediates activation of the Drosophila integrator complex. The Journal of biological chemistry 28 23288851
2023 Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer. Cancer research 25 36548402
2017 Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways. BMC genomics 19 28335732
2017 The treatment of wastewater containing pharmaceuticals in microcosm constructed wetlands: the occurrence of integrons (int1-2) and associated resistance genes (sul1-3, qacEΔ1). Environmental science and pollution research international 11 28493189
2025 Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal. eLife 4 40207620
2026 Integrator subunit INTS12 links ribotoxic stress to transcription-coupled nucleotide excision repair. Nature structural & molecular biology 1 41748916
2025 Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal. bioRxiv : the preprint server for biology 1 39257755
2025 Exploring genetic loci linked to COVID-19 severity and immune response through multi-trait GWAS analyses. Frontiers in genetics 1 40034745
2026 Allogeneic stem cell transplantation for myelofibrosis in the modern era: Single-center outcomes with DIPSS risk stratification. Blood research 0 42234227

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