Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation

Transcriptional adaptation (TA) is a genetic robustness mechanism through which mutant messenger RNA (mRNA) decay induces sequence-dependent up-regulation of so-called adapting genes. How cytoplasmically generated mRNA fragments affect nuclear transcription remains poorly understood. Using genome-wide CRISPR screens, we uncover ILF3 as an RNA binding protein connecting cytoplasmic mRNA decay and transcription during TA and show that it is required for a range of TA substrates. ILF3 is enriched at adapting genes' RNAs, and its artificial recruitment through dCas13 promotes gene expression. Using tiling oligonucleotide screens, we identify trigger RNA fragments that activate adapting genes when introduced into…

• HF
  Hypothesis Fund
• HH
  Howard Hughes Medical Institute
• M
  Moderna
• BF
  Bayer Foundation
• NO
  NIH Office of the Director

  Award: K99HG014205