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The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

Dylane Detilleux1, Peggy Raynaud1, Berengere Pradet-Balade1

  • 1CRBM, University of Montpellier, CNRS, Montpellier, France.

Elife
|March 4, 2022
PubMed

Insights

The triple T (TTT) complex subunit TELO2 aids TRRAP protein assembly into crucial transcription factors. TRRAP unexpectedly represses interferon genes, potentially contributing to colorectal cancer progression.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Transcription factors like TRRAP are vital for cellular responses.
  • TRRAP is part of SAGA and TIP60 complexes, but its pseudokinase nature is unique.
  • The triple T (TTT) complex is essential for stabilizing phosphoinositide 3 kinase-related kinases (PIKKs).

Purpose of the Study:

  • To investigate the role of the TTT complex subunit TELO2 in TRRAP assembly and function.
  • To explore the impact of TELO2 and TRRAP on gene expression in colorectal cancer cells.
  • To uncover novel functions of TRRAP in transcriptional regulation.

Main Methods:

  • Utilized endogenous auxin-inducible degron alleles in human colorectal cancer cells.
  • Performed transcriptomic analysis to assess gene expression changes.
  • Employed nascent RNA sequencing, CUT&RUN, ChIP, and kinetic analyses.

Main Results:

  • TELO2 promotes the assembly of TRRAP into SAGA and TIP60 complexes.
  • TELO2 influences TRRAP's regulation of MYC target genes.
  • Depletion of TELO2 and TRRAP unexpectedly increases type I interferon gene expression.
  • TRRAP directly represses the transcription of IRF9, a key interferon pathway regulator.

Conclusions:

  • TELO2 is crucial for TRRAP's role in transcription activation and regulation.
  • TRRAP exhibits a previously unrecognized function as a transcriptional repressor of interferon genes.
  • This novel repressive role of TRRAP may contribute to its tumorigenic activity in colorectal cancer.
Keywords:
PIKKchaperonechromosomescolorectal cancergene expressionhumaninterferontranscription

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