INTS13

INTS13 is a subunit of the Integrator complex that nucleates a separable auxiliary sub-module with INTS10, INTS14, and INTS15, coupling this module to the catalytic core of the complex and to gene-specific transcriptional regulation (PMID:32647223, PMID:36920904). Structurally, INTS13 forms a strongly entwined heterodimer with INTS14 that resembles the Ku70-Ku80 DNA-repair complex and confers nucleic acid-binding activity to the module, with a preference for RNA hairpins (PMID:32647223). A conserved C-terminal motif of INTS13 directly tethers the sub-module to the Integrator cleavage module, an interaction required for snRNA processing and disrupted by germline variants (p.S652L, p.K668Nfs*9) (PMID:32647223, PMID:36229431). Within the assembled Integrator-PP2A complex, the INTS10-INTS13-INTS14-INTS15 module adopts a scorpion-tail-shaped architecture whose protruding 'sting' opens the DSIF DNA clamp to promote promoter-proximal RNA Pol II termination after pausing (PMID:32647223, PMID:38570683). Beyond its catalytic coupling role, INTS13 serves as a recruitment platform that links Integrator to sequence-specific transcription factors—including EGR1/2 with their cofactor NAB2, ZNF655, and ZBTB26—directing Integrator to specific promoters and enhancers, sustaining active chromatin states, and driving defined transcriptional programs such as monocytic/macrophagic differentiation (PMID:30008316, PMID:38823386, PMID:42219880). INTS13 is also required for ciliogenesis in human cells and Xenopus embryos (PMID:36229431), and its Drosophila ortholog (Mat89Bb) is a PAN GU kinase substrate with a conserved role in cell cycle control (PMID:15737938).

1. 2005 High

   Before its incorporation into Integrator was known, the gene's ortholog was placed in cell-cycle control by identifying it as a kinase substrate whose loss causes polyploidy across species.

   Evidence In vitro expression cloning screen for PAN GU kinase substrates plus RNAi in Drosophila and HeLa and morpholino knockdown in Xenopus

   PMID:15737938

   Open questions at the time

   • Did not connect the protein to transcription or the Integrator complex
   • Mechanism by which phosphorylation controls cell-cycle/ploidy not defined
   • No molecular target or biochemical activity assigned
2. 2018 High

   Established that INTS13 acts as a semi-autonomous Integrator sub-module that targets enhancers via specific transcription factors to drive a defined differentiation program.

   Evidence ChIP-seq, chromatin looping assays, siRNA/shRNA depletion in cell lines and primary human progenitors, and co-IP with EGR1/2 and NAB2

   PMID:30008316

   Open questions at the time

   • Structural basis of TF recruitment unresolved
   • Whether the catalytic core is required for the enhancer/differentiation function not dissected
   • Generality beyond monocytic differentiation unknown
3. 2020 High

   Defined the molecular architecture of the sub-module and the physical link to the cleavage core, explaining how INTS13 contributes to snRNA processing and termination.

   Evidence Crystal structure of INTS13-INTS14, in vitro nucleic acid binding assays, co-purification, and C-terminal motif mutagenesis with snRNA processing and termination readouts

   PMID:32647223

   Open questions at the time

   • Functional consequence of RNA-hairpin binding in cells not established
   • Significance of Ku-like fold for activity unclear
   • How the module is positioned relative to Pol II not yet visualized
4. 2022 High

   Linked the C-terminal cleavage-module interaction to human disease and a new cellular process by showing INTS13 is required for ciliogenesis.

   Evidence Patient homozygosity mapping/exome sequencing, co-IP with C-terminal mutagenesis, siRNA depletion with ciliogenesis readout in human cells, and Xenopus knockdown

   PMID:36229431

   Open questions at the time

   • Which ciliary genes are directly Integrator-regulated not defined
   • Whether cilia phenotype reflects transcription termination versus another role unclear
   • Connection between cleavage-module binding and ciliary gene control mechanistic detail absent
5. 2023 Medium

   Identified INTS15 as a fourth member of the module and connected the module to RNA Pol II pausing regulation.

   Evidence Mass-spectrometry proteomics, AlphaFold2 prediction, and ChIP-seq/PRO-seq for pausing

   PMID:36920904

   Open questions at the time

   • AlphaFold2 interface predictions await experimental structure
   • Direct contribution of INTS13 versus INTS15 to pausing not separated
   • Subset of genes affected not mechanistically explained
6. 2024 High

   Provided direct structural mechanism: the module forms a scorpion-tail arm whose tip opens the DSIF clamp to drive promoter-proximal termination.

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

   PMID:38570683

   Open questions at the time

   • DSIF-clamp opening shown structurally but not validated by mutagenesis of INTS13 contacts
   • Trigger that engages the 'sting' at specific genes unknown
7. 2024 Medium

   Expanded the recruitment-platform model by identifying a transcription factor (ZNF655) predicted to bind INTS13 within assembled Integrator and modulate locus-specific stability.

   Evidence Cryo-EM of INTS10/13/14/15 and INTS5/8/10/15 sub-complexes plus an in silico AlphaFold2 screen of >1,500 TFs and structural modeling

   PMID:38823386

   Open questions at the time

   • ZNF655 interaction is in silico and lacks direct experimental binding validation
   • Functional consequence of ZNF655-INTS13 binding not tested
   • Generality of TF-platform model across loci unproven
8. 2025 Medium

   Placed INTS13 in a cancer signaling axis as both a regulated gene and an upstream effector of a downstream RNA-binding protein.

   Evidence ChIP for ZNF384 promoter binding, CRISPR/Cas9 knockout and siRNA silencing of INTS13, hnRNPC rescue, and xenograft model in cervical cancer cells

   PMID:41429980

   Open questions at the time

   • Mechanism by which INTS13 regulates hnRNPC (transcriptional vs processing) not defined
   • Whether the axis depends on Integrator catalytic activity unknown
   • Single-cancer-context finding without broader validation
9. 2026 Medium

   Demonstrated a second TF (ZBTB26) physically recruits Integrator via INTS10/INTS13 to co-occupied promoters/enhancers, reinforcing INTS13 as a TF-docking platform driving gene programs.

   Evidence Reciprocal co-IP, ChIP-seq co-occupancy, ZBTB26 depletion with Integrator-recruitment readout, and transcriptional profiling

   PMID:42219880

   Open questions at the time

   • Single-lab study without independent replication
   • Relative contributions of INTS10 versus INTS13 to ZBTB26 binding not separated
   • Whether recruitment alters termination versus activation locally unresolved

• How INTS13's distinct activities—catalytic coupling to the cleavage module, DSIF-clamp opening, RNA-hairpin binding, and gene-specific TF docking—are coordinated and selectively deployed at individual loci remains unresolved.
• No unifying model linking the structural termination role with locus-specific TF recruitment
• Determinants of which genes use INTS13 as an enhancer platform versus a termination factor unknown
• Direct biochemical role of INTS13 RNA-hairpin binding in vivo undefined