Affinage

INTS7

Integrator complex subunit 7 · UniProt Q9NVH2

Round 2 corrected
Length
962 aa
Mass
106.8 kDa
Annotated
2026-04-28
39 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTS7 is a backbone structural subunit of the metazoan Integrator complex, a multiprotein assembly that associates with the RNA polymerase II C-terminal domain to mediate 3′-end processing of small nuclear RNAs and promote transcription termination (PMID:16239144, PMID:33243860). Cryo-EM structures show that INTS7 resides in the backbone module of the Integrator–PP2A (INTAC) complex, which couples nascent RNA cleavage by the endonuclease module with CTD dephosphorylation by PP2A, engaging paused Pol II together with DSIF and NELF to exclude elongation factors and enforce premature termination (PMID:33243860, PMID:34762484). Loss of INTS7 in mouse embryonic stem cells increases DNA damage, triggers Kap1 phosphorylation and chromatin opening at endogenous retrovirus loci, and activates the p53–Dux transcriptional axis to derepress MERVL, linking Integrator backbone integrity to heterochromatin maintenance and developmental potency (PMID:40842237). Outside its Integrator role, INTS7 is stabilized by BAG3 (which prevents its ubiquitin-dependent degradation) and interacts with the peroxisomal transporter ABCD3 to suppress reactive oxygen species and promote osteoblastic differentiation of bone marrow mesenchymal stem cells (PMID:37576499, PMID:34880777).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2005 High

    Identification of INTS7 as a subunit of the Integrator complex resolved the molecular machinery responsible for snRNA 3′-end processing associated with the Pol II CTD, establishing its fundamental functional context.

    Evidence Affinity purification/mass spectrometry of the Integrator complex with ChIP and snRNA processing assays in human cells

    PMID:16239144

    Open questions at the time
    • Precise structural position of INTS7 within the complex unknown
    • Direct contribution of INTS7 versus other subunits to snRNA processing not delineated
  2. 2007 Medium

    Independent AP-MS surveys replicated INTS7 as a stable component of the endogenous Integrator complex, solidifying its assignment as a constitutive subunit rather than a transient interactor.

    Evidence Systematic AP-MS of transcription and RNA processing machinery in human nuclear extracts

    PMID:17643375 PMID:20133760

    Open questions at the time
    • Stoichiometry within the complex not determined
    • Functional consequence of INTS7 depletion alone not tested
  3. 2009 Medium

    Genetic loss-of-function studies of the Drosophila ortholog deflated demonstrated that INTS7 is essential for metazoan development and cell proliferation, extending the gene's significance beyond snRNA processing.

    Evidence Four loss-of-function alleles in Drosophila with developmental phenotyping and GFP localization

    PMID:19326441

    Open questions at the time
    • Whether developmental defects arise from snRNA processing failure or other Integrator functions was unclear
    • No mammalian knockout phenotype yet reported
  4. 2011 Medium

    A genome-wide DNA damage response screen revealed that INTS7 is recruited to sites of DNA damage, implicating the Integrator backbone in genome maintenance beyond transcription.

    Evidence Functional genomic screen for damage-induced cell cycle arrest with imaging of recruitment to damage foci

    PMID:21659603

    Open questions at the time
    • Mechanism of recruitment to damage sites unknown
    • Whether INTS7 acts at damage sites as part of Integrator or independently was unresolved
  5. 2020 High

    Near-atomic cryo-EM structures placed INTS7 within the backbone module of the INTAC complex and revealed how Integrator integrates RNA endonuclease and PP2A-mediated CTD phosphatase activities into a single structural assembly for transcription regulation.

    Evidence Cryo-EM at 3.5 Å resolution with biochemical CTD dephosphorylation assays

    PMID:33243860

    Open questions at the time
    • INTS7-specific contacts within the backbone not fully resolved at side-chain level
    • No reconstitution of INTAC lacking INTS7 to test its structural necessity
  6. 2021 High

    Structural determination of the Integrator–PP2A–Pol II pretermination complex showed how the backbone module containing INTS7 scaffolds the endonuclease and phosphatase near paused Pol II to exclude elongation factors and enable transcription termination.

    Evidence Cryo-EM of the pretermination complex with structural analysis of subunit interfaces

    PMID:34762484

    Open questions at the time
    • Direct mutagenesis of INTS7 interface residues not performed
    • Dynamics of INTS7 engagement during the transition from pausing to termination unknown
  7. 2021 Medium

    Discovery that INTS7 directly interacts with the peroxisomal ABC transporter ABCD3 to suppress oxidative stress and promote osteoblastic differentiation in BM-MSCs revealed a functional role outside canonical Integrator-mediated transcription termination.

    Evidence Reciprocal co-immunoprecipitation, siRNA knockdown, ROS quantification, and differentiation assays in mouse BM-MSCs

    PMID:34880777

    Open questions at the time
    • Whether the INTS7–ABCD3 interaction occurs independently of the Integrator complex is untested
    • Structural basis and binding interface unknown
    • Mechanism by which oxidative stress is suppressed not molecularly defined
  8. 2023 Medium

    BAG3 was shown to stabilize INTS7 by preventing its ubiquitin-dependent degradation, placing INTS7 protein turnover downstream of a co-chaperone pathway and linking it to oxidative stress resistance in BM-MSCs.

    Evidence Co-immunoprecipitation, ubiquitination assay, protein half-life measurement, and INTS7 rescue experiment in BM-MSCs

    PMID:37576499

    Open questions at the time
    • E3 ligase responsible for INTS7 ubiquitination not identified
    • Whether BAG3 regulation of INTS7 affects Integrator complex assembly or only non-Integrator functions is unknown
  9. 2025 High

    Knockout of Ints7 in mouse ESCs established a mechanistic circuit in which Integrator backbone loss triggers Kap1 phosphorylation, chromatin opening at endogenous retroviruses, and p53–Dux-driven MERVL derepression coupled with caspase-3-mediated anastasis, connecting Integrator to heterochromatin maintenance and developmental potency.

    Evidence CRISPR knockout in mESCs with ATAC-seq, Kap1 phosphorylation analysis, p53–Dux transcriptional profiling, and caspase-3 activation assays

    PMID:40842237

    Open questions at the time
    • Whether INTS7-specific loss versus general Integrator disruption is responsible for MERVL derepression is not resolved
    • Upstream kinase phosphorylating Kap1 upon INTS7 loss not identified
    • Relevance to human ESCs or in vivo embryonic development untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific structural contacts of INTS7 within the Integrator backbone, its individual contribution to complex assembly and enzymatic functions (versus other backbone subunits), and whether its non-Integrator activities (ABCD3, BAG3 axis) operate through independent protein pools remain unresolved.
  • No reconstituted INTAC lacking only INTS7 to define its unique structural contribution
  • No separation-of-function mutant distinguishing Integrator-dependent from -independent roles
  • E3 ligase and degron motif for INTS7 ubiquitination unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2 R-HSA-4839726 Chromatin organization 1
Partners
ABCD3BAG3INTS1INTS11INTS4PP2A
Complex memberships
Integrator complexIntegrator-PP2A (INTAC)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 INTS7 (named KIAA0999/INT7) was identified as one of at least 12 novel subunits of the Integrator complex, a large multiprotein assembly that associates with the C-terminal domain (CTD) of RNA polymerase II and mediates 3'-end processing of small nuclear RNAs (snRNAs). The Integrator complex was purified by affinity purification and its subunits identified by mass spectrometry; Integrator was shown to be recruited to U1 and U2 snRNA genes and required for their 3' end processing. Affinity purification and mass spectrometry; ChIP at snRNA genes; in vitro and cell-based snRNA processing assays Cell High 16239144
2007 INTS7 was identified as a component of the human Integrator complex in a systematic affinity purification/mass spectrometry survey of the transcription and RNA processing machinery, confirming its membership in the complex associated with RNA polymerase II. Protein affinity purification coupled to mass spectrometry Molecular cell Medium 17643375
2008 The CDT2-INTS7 intergenic region (246 bp in human) was shown to function as a bidirectional promoter. Transcription factors E2F1–E2F4 up-regulated expression from this promoter in the CDT2 direction only, while B-Myb, c-Myb, and p53 down-regulated expression in the INTS7 direction. Overexpressed E2F1 increased CDT2 but not INTS7 mRNA, demonstrating asymmetric regulation of the two genes from the shared promoter. Luciferase reporter assays, adenoviral-mediated E2F1 overexpression, RT-PCR in human and mouse tissues PloS one Medium 18213392
2009 The Drosophila ortholog of INTS7, encoded by the gene deflated (CG18176), is essential for normal development. Loss-of-function mutations caused pleiotropic developmental defects including a pupal lethal abdominal phenotype, consistent with perturbation of cell signaling or cell proliferation. GFP-tagged Deflated protein was found to be predominantly nuclear, and deflated mRNA was detected at low levels in proliferating cells, establishing a requirement for this Ints7 homolog in normal cell signaling and proliferation. Generation and analysis of four loss-of-function alleles; GFP-tagging and imaging; in situ hybridization Developmental dynamics Medium 19326441
2010 Novel components of the endogenous human Integrator complex, including INTS7, were consistently purified and identified by immunoprecipitation/mass spectrometry from nuclear extracts, further establishing INTS7 as a stable core component of the Integrator complex. IP/MS with spectral count-based specificity filters targeting endogenous complexes Proceedings of the National Academy of Sciences of the United States of America Medium 20133760
2011 INTS7 (the RNA processing protein) was identified in a genome-wide DNA damage response screen and found to be recruited to sites of DNA damage, implicating INTS7 in the DNA damage response pathway alongside factors such as CLOCK and RHINO. Functional genomic screen for damage-induced cell cycle arrest; recruitment to DNA damage sites by imaging Science (New York, N.Y.) Medium 21659603
2020 Cryo-EM structural analysis identified the INTAC complex — Integrator bound to the PP2A core enzyme (PP2A-AC). INTS7 is part of the backbone module of the nine-subunit Integrator scaffold that, together with the shoulder module, forms a cruciform central scaffold. The INTAC complex dephosphorylates the RNA Pol II CTD at Ser-2, -5, and -7, integrating dual enzymatic activities (RNA cleavage via the endonuclease module and CTD dephosphorylation via PP2A) into a single structural assembly. Cryo-EM at 3.5 Å resolution; biochemical dephosphorylation assays of Pol II CTD Science (New York, N.Y.) High 33243860
2021 Cryo-EM structure of the Integrator-PP2A pretermination complex bound to paused RNA Pol II revealed the structural basis of Integrator-mediated transcription regulation. INTS7 is part of the backbone module. Integrator engages Pol II and pausing factors DSIF and NELF to exclude elongation factors SPT6 and PAF1C. PP2A is positioned to counteract Pol II CTD phosphorylation, and the Integrator endonuclease docks at the RNA exit site to cleave nascent RNA ~20 nt from the active site, enabling transcription termination. Cryo-EM structure of pretermination complex; structural analysis of subunit interfaces Science (New York, N.Y.) High 34762484
2021 INTS7 directly interacts with ABCD3 (also known as PMP70) in mouse bone marrow mesenchymal stem cells (BM-MSCs), and this INTS7-ABCD3 interaction is required for BM-MSC proliferation and osteoblastic differentiation. Knockdown of either INTS7 or ABCD3 (but not HDLBP) impaired proliferation, induced apoptosis, decreased osteoblastic differentiation, and accelerated adipogenic differentiation. Mechanistically, INTS7 and ABCD3 suppression elevated reactive oxygen species (ROS) and γ-H2AX levels while reducing antioxidants, indicating that the INTS7-ABCD3 complex promotes BM-MSC expansion and osteoblastic fate partly by suppressing oxidative stress. siRNA knockdown; co-immunoprecipitation; CCK-8 proliferation assay; Alizarin Red S and Oil Red O differentiation staining; ROS and γ-H2AX quantification Frontiers in physiology Medium 34880777
2022 OpenCell systematic endogenous tagging of human proteins confirmed nuclear localization of INTS7 and identified its interaction partners by mass spectrometry, consistent with its role as a nuclear component of the Integrator complex. CRISPR-based endogenous GFP tagging; confocal live-cell imaging; affinity purification mass spectrometry Science (New York, N.Y.) Medium 35271311
2023 BAG3 directly interacts with INTS7 in BM-MSCs, as demonstrated by co-immunoprecipitation. BAG3 knockdown decreased INTS7 protein levels and promoted its ubiquitination, indicating that BAG3 stabilizes INTS7 by protecting it from proteasomal degradation. The resulting decrease in INTS7 upon BAG3 loss increased ROS and DNA damage in BM-MSCs, and re-expression of INTS7 or addition of an antioxidant rescued the proliferation defect caused by BAG3 depletion, placing INTS7 downstream of BAG3 in a pathway controlling oxidative stress and cell expansion. Co-immunoprecipitation; protein half-life assay; western blotting for ubiquitination; CCK-8 and colony formation assays; flow cytometry; TUNEL assay; INTS7 rescue experiment PeerJ Medium 37576499
2025 Loss of Ints7 (a backbone subunit of the Integrator complex) in mouse embryonic stem cells (mESCs) increased DNA damage and triggered expression of the endogenous retrovirus MERVL. Mechanistically, Ints7 depletion induced phosphorylation of Kap1 (a heterochromatin maintenance factor), increased chromatin accessibility at MERVL loci, and activated the p53-Dux transcriptional axis to drive MERVL transcription. Furthermore, DNA damage-induced MERVL resurgence was accompanied by caspase-3 cleavage and a process of anastasis (cell survival after transient apoptotic signaling), linking Ints7 to a cellular circuit integrating DNA damage response and developmental potential of stem cells. Genome-wide CRISPR knockout screen; Ints7 knockout mESCs; chromatin accessibility assays (ATAC-seq); Kap1 phosphorylation analysis; p53-Dux axis transcriptional analysis; caspase-3 activation assay Nucleic acids research High 40842237
2025 siRNA-mediated knockdown of INTS7 in lung adenocarcinoma cell lines significantly inhibited cell proliferation and induced cell cycle arrest, as measured by CCK-8 assay and flow cytometry, establishing a functional role for INTS7 in promoting cell cycle progression in LUAD cells. siRNA knockdown; CCK-8 proliferation assay; flow cytometry cell cycle analysis Briefings in functional genomics Low 40875878

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2005 Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 443 16239144
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2011 A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science (New York, N.Y.) 183 21659603
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2021 The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer. Cell 152 34004147
2020 Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase. Science (New York, N.Y.) 151 33243860
2001 Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. Genome research 151 11230166
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2014 Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nature communications 123 25187353
2021 Structural basis of Integrator-mediated transcription regulation. Science (New York, N.Y.) 112 34762484
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2010 Streamlined analysis schema for high-throughput identification of endogenous protein complexes. Proceedings of the National Academy of Sciences of the United States of America 102 20133760
2012 Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells. Journal of cellular physiology 46 21732367
2005 A new common integration site, Int7, for the mouse mammary tumor virus in mouse mammary tumors identifies a gene whose product has furin-like and thrombospondin-like sequences. Journal of virology 43 16014973
2021 INTS7-ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress. Frontiers in physiology 26 34880777
2009 Phenotypic analysis of deflated/Ints7 function in Drosophila development. Developmental dynamics : an official publication of the American Association of Anatomists 25 19326441
2008 Transcriptional regulation of an evolutionary conserved intergenic region of CDT2-INTS7. PloS one 15 18213392
2021 Overexpression and diagnostic significance of INTS7 in lung adenocarcinoma and its effects on tumor microenvironment. International immunopharmacology 10 34781123
2023 BAG3 regulates bone marrow mesenchymal stem cell proliferation by targeting INTS7. PeerJ 3 37576499
2025 Ints7 deficiency activates DNA damage response to elicit resurgence of endogenous retrovirus MERVL and anastasis of embryonic stem cells. Nucleic acids research 0 40842237
2025 INTS7 modulates cell proliferation and apoptosis via promoting cell cycle progression in lung adenocarcinoma. Briefings in functional genomics 0 40875878