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Updated: May 31, 2025

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
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Coding relationship links RNA G-quadruplexes and protein RGG motifs in RNA-binding protein autoregulation.

Marlene Adlhart1,2, Daniel Hoffmann1,2, Anton A Polyansky1,2

  • 1Max Perutz Labs, Vienna Biocenter Campus, Vienna 1030, Austria.

Proceedings of the National Academy of Sciences of the United States of America
|January 23, 2025
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Summary

Guanine-rich RNA G-quadruplexes (rG4s) can encode arginine-glycine-rich motifs (RGG motifs) in messenger RNAs (mRNAs). This genetic code feature links RNA structure to protein binding, potentially regulating gene expression.

Keywords:
RGG motifRNA G-quadruplexRNA-binding proteinsautoregulationgenetic code

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Guanine-rich RNA sequences form G-quadruplexes (rG4s).
  • RNA-binding proteins (RBPs) with arginine-glycine-rich motifs (RGG motifs) recognize rG4s.
  • Arginine and glycine codons are guanine-rich.

Purpose of the Study:

  • To investigate the relationship between rG4s and RGG motif encoding in autogenous messenger RNAs (mRNAs).
  • To determine if this relationship is hardwired in the genetic code and impacts protein-RNA interactions.
  • To identify specific RBPs involved in these interactions.

Main Methods:

  • Transcriptome-wide analysis of rG4 datasets.
  • Use of randomized genetic codes to assess the coding relationship.
  • Analysis of enhanced crosslinking and immunoprecipitation (eCLIP) data.

Main Results:

  • Hundreds of human RGG motifs are encoded by rG4s, particularly longer motifs.
  • The rG4/RGG coding relationship is a consequence of the universal genetic code.
  • Proteins with rG4-encoded RGG motifs show increased RNA binding.
  • Specific RBPs (FUS, FMRP, G3BP1) interact with autogenous mRNAs at these sites.

Conclusions:

  • A mechanism exists where RNA structure (rG4s) dictates protein-binding motif (RGG) encoding within the same mRNA.
  • This RNA G-quadruplex/RGG motif coding is embedded in the genetic code.
  • This interaction may establish autoregulatory feedback loops for gene expression control.