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RNA G-quadruplexes promote codon repeat-associated ribosomal frameshifting in human genes.

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Programmed ribosomal frameshifting (PRF) in humans is enhanced by RNA G-quadruplexes (rG4s) near codon repeats. This discovery reveals a key mechanism for translational recoding and trans-frame protein production in human cells.

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Area of Science:

  • Molecular Biology
  • Genetics
  • RNA Biology

Background:

  • Programmed ribosomal frameshifting (PRF) is a translational recoding process.
  • Previously considered rare in eukaryotes, PRF occurs extensively in humans.
  • Codon repeats signal trans-frame protein production in human tissues.

Purpose of the Study:

  • To elucidate the molecular mechanism of codon repeat-associated ribosomal frameshifting (CRFS).
  • To identify factors enhancing PRF in human genes.

Main Methods:

  • Developed a reporter system using the HDAC1 CRFS sequence for +1 frameshifting at (UAC)3 repeats.
  • Performed whole-genome CRISPR screening to identify PRF enhancers.
  • Investigated the role of RNA G-quadruplexes (rG4s) in PRF.

Main Results:

  • Identified RBM4, an RNA-binding protein interacting with rG4s, as a PRF enhancer for HDAC1 mRNA.
  • Disrupting the rG4 downstream of the (UAC)3 repeat reduced frameshifting.
  • rG4-stabilizing compounds and other rG4 structures enhanced frameshifting.
  • Engineered rG4 sequences significantly promoted frameshifting when inserted into other genes.

Conclusions:

  • RNA G-quadruplexes (rG4s) are critical elements for CRFS.
  • rG4s are significantly enriched downstream of codon repeats in the human genome.
  • This rG4-mediated mechanism likely contributes to extensive ribosomal frameshifting in humans.