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10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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INTS6
integrator complex subunit 6
Chromosome 13 · 13q14.3
NCBI Gene: 26512Ensembl: ENSG00000102786.15HGNC: HGNC:14879UniProt: B3KU90
84PubMed Papers
20Diseases
0Drugs
1Pathogenic Variants
FUNCTIONAL ROLE
Highly Constrained
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
INTAC complexprotein bindingprotein-macromolecule adaptor activitysnRNA processingneurodegenerative diseaseoptic neuritisneuropathygestational diabetes
✦AI Summary

INTS6 (integrator complex subunit 6) is a core component of the Integrator complex, a multiprotein machine that terminates RNA polymerase II (Pol II) transcription at promoter-proximal pause sites 12. INTS6 functions as a molecular adapter that recruits protein phosphatase 2A (PP2A) to the Integrator core complex, enabling dephosphorylation of Pol II and associated factors like DSIF and SPT5 12. The Integrator complex also degrades nascent RNA transcripts and removes Pol II from DNA, serving as a quality checkpoint to eliminate poorly configured transcription units, including non-coding RNAs such as snRNAs, eRNAs, and lncRNAs 34. Additionally, INTS6 associates with the SOSS1 complex at DNA double-strand breaks, facilitating PP2A recruitment and DNA:RNA hybrid resolution 5. Beyond transcriptional control, INTS6 exhibits tumor suppressor activity; loss of INTS6 confers resistance to CDK9 inhibition in cancer cells and promotes hepatocellular steatosis via β-catenin-PPARγ signaling 26. Recently, INTS6 mutations were identified as causing neurodevelopmental disorders characterized by language delays, autism, and intellectual disability, with cellular studies revealing disrupted neurogenesis and impaired synaptic gene expression 7.

Sources cited
1
INTS6 as adapter for PP2A recruitment to Integrator complex and Pol II CTD dephosphorylation
PMID: 33243860
2
INTS6-mediated PP2A recruitment antagonizes CDK9; loss of INTS6 causes CDK9 inhibitor resistance in cancer
PMID: 34004147
3
Structural basis showing INTS6 blocks PP2A active site in inactive Integrator-PP2A complex
PMID: 38570683
4
Integrator complex removes defective Pol II at promoter-proximal pause checkpoint
PMID: 39504960
5
INTS6-SOSS1 tetrameric complex at DSBs facilitates PP2A recruitment and DNA:RNA hybrid resolution
PMID: 39445827
6
INTS6 expression correlates with hepatocellular steatosis via β-catenin-PPARγ axis
PMID: 38981571
7
INTS6 variants cause neurodevelopmental disorders with deficits in neurogenesis, synaptic development, and behavior
PMID: 40966122
8
INTS6 exhibits tumor suppressor activity by inhibiting prostate cancer cell growth and altering Wnt signaling
PMID: 19906297
Disease Associationsⓘ20
neurodegenerative diseaseOpen Targets
0.50Moderate
optic neuritisOpen Targets
0.29Weak
neuropathyOpen Targets
0.28Weak
gestational diabetesOpen Targets
0.28Weak
Abnormality of the skeletal systemOpen Targets
0.27Weak
lysosomal storage diseaseOpen Targets
0.21Weak
endometrial carcinomaOpen Targets
0.15Weak
autism spectrum disorderOpen Targets
0.12Weak
hepatocellular carcinomaOpen Targets
0.10Weak
prostate cancerOpen Targets
0.09Suggestive
neoplasmOpen Targets
0.09Suggestive
Neurodevelopmental delayOpen Targets
0.04Suggestive
breast cancerOpen Targets
0.04Suggestive
non-small cell lung carcinomaOpen Targets
0.03Suggestive
lung carcinomaOpen Targets
0.02Suggestive
colorectal neoplasmOpen Targets
0.02Suggestive
nasopharyngeal carcinomaOpen Targets
0.02Suggestive
cancerOpen Targets
0.02Suggestive
retinoblastomaOpen Targets
0.01Suggestive
colorectal cancerOpen Targets
0.01Suggestive
Pathogenic Variants1
NM_012141.3(INTS6):c.682C>G (p.Gln228Glu)Likely pathogenic
INTS6-associated neurodevelopmental disorder
★☆☆☆2025→ Residue 228
View on ClinVar ↗
Related Genes
POLR2KProtein interaction100%SUPT5HProtein interaction100%POLR2FProtein interaction100%POLR2IProtein interaction100%INTS13Protein interaction100%POLR2AProtein interaction100%
Tissue Expression6 tissues
Liver
100%
Bone Marrow
76%
Ovary
71%
Heart
70%
Lung
62%
Brain
51%
Gene Interaction Network
Click a node to explore
INTS6POLR2KSUPT5HPOLR2FPOLR2IINTS13POLR2A
PROTEIN STRUCTURE
Preparing viewer…
PDB7BV7 · 2.40 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.23Highly Constrained
pLIⓘ
1.00Intolerant
Observed/Expected LoF0.14 [0.08–0.23]
RankingsWhere INTS6 stands among ~20K protein-coding genes
  • #5,672of 20,598
    Most Researched84
  • #4,945of 5,498
    Most Pathogenic Variants1
  • #638of 17,882
    Most Constrained (LOEUF)0.23 · top 5%
Genes detectedINTS6
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.
PMID: 34004147
Cell · 2021
1.00
2
Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development.
PMID: 40966122
J Clin Invest · 2025
0.90
3
Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint.
PMID: 39504960
Mol Cell · 2024
0.80
4
Integrator complex subunit 6 promotes hepatocellular steatosis via β-catenin-PPARγ axis.
PMID: 38981571
Biochim Biophys Acta Mol Cell Biol Lipids · 2024
0.70
5
Structural basis of Integrator-dependent RNA polymerase II termination.
PMID: 38570683
Nature · 2024
0.60