INTS14

INTS14 is a core subunit of the Integrator complex that functions within a discrete nucleic acid-binding submodule controlling RNA Polymerase II promoter-proximal transcription termination (PMID:32647223, PMID:38570683). Together with INTS10 and INTS13, INTS14 forms a separable functional module; the INTS13-INTS14 heterodimer is a strongly entwined, chain-interlinked pair structurally homologous to the Ku70-Ku80 DNA repair complex, and the assembled module binds nucleic acids with a preference for RNA hairpins over DNA (PMID:32647223). Within the complete Integrator-PP2A complex, INTS10-INTS13-INTS14 (with INTS15) form a scorpion-tail-shaped module whose 'sting' region opens the DSIF DNA clamp on paused Pol II, facilitating polymerase removal from the template and transcription termination (PMID:38570683). INTS13's conserved C-terminal motif contacts the Integrator cleavage module, positioning this submodule to bring the cleavage machinery and target transcripts into proximity, and the module additionally plays an accessory role in snRNA 3'-end maturation (PMID:32647223). Beyond its role in transcription termination, INTS14 positively regulates MYC promoter activity, with its depletion reducing MYC expression and inducing G0/G1 arrest (PMID:35887071).

1. 2020 High

   Established that INTS14 is not a standalone factor but part of a separable, structurally distinct Integrator submodule, defining its molecular architecture and nucleic-acid-binding character.

   Evidence X-ray crystallography of the INTS13-INTS14 heterodimer with biochemical reconstitution, nucleic acid binding assays, cross-linking mass spectrometry, and functional snRNA/termination assays

   PMID:32647223

   Open questions at the time

   • The functional significance of the Ku-like fold for transcription is not mechanistically resolved
   • How RNA hairpin recognition is coupled to cleavage module activity is not directly demonstrated
2. 2022 Medium

   Connected INTS14 to protein-coding gene regulation by showing it positively controls MYC expression and cell cycle progression, extending its role beyond snRNA processing.

   Evidence CRISPR screen for MYC promoter regulators, siRNA knockdown of INTS14, qRT-PCR/western blot for MYC, and cell cycle analysis in prostate cell lines

   PMID:35887071

   Open questions at the time

   • Single lab with limited mechanistic detail on how INTS14 activates the MYC promoter
   • Whether MYC regulation requires the INTS14 termination function or a separate activity is unknown
3. 2024 High

   Resolved how the INTS14-containing module physically executes termination by visualizing its spatial relationship to the paused Pol II machinery in defined functional states.

   Evidence Cryo-EM structures of pre-termination, post-termination, and free Integrator-PP2A complexes

   PMID:38570683

   Open questions at the time

   • Dynamics and timing of DSIF clamp opening are inferred from static states
   • Determinants selecting which paused transcripts are terminated are not defined

• How INTS14's submodule integrates RNA hairpin recognition, cleavage module recruitment, and MYC promoter activation into a unified regulatory logic remains unresolved.
• No direct link established between hairpin binding and gene-specific selectivity
• Mechanism connecting termination function to positive MYC regulation is uncharacterized