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UPF1 regulates mRNA stability by sensing poorly translated coding sequences.

Damir Musaev1, Mario Abdelmessih2, Charles E Vejnar1

  • 1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.

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|April 16, 2024
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Summary

mRNA stability is regulated by translation initiation, upstream open reading frames (uORFs), and open reading frame (ORF) length. The protein Upf1 surveils poorly translated ORFs, unifying mRNA decay pathways like ORF-mediated decay (OMD).

Keywords:
CP: Molecular biologyGC-richnessNMDORF lengthUPF1mRNA decaymRNA homeostasismRNA translationoORFuORF

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Area of Science:

  • Molecular Biology
  • Gene Expression Regulation
  • RNA Biology

Background:

  • Post-transcriptional mRNA regulation is crucial for gene expression.
  • The interplay between cis-elements and mRNA translation in regulating mRNA stability remains poorly understood.

Purpose of the Study:

  • To investigate how various mRNA features and translation efficiency collectively influence mRNA stability.
  • To elucidate the role of the protein Upf1 in mRNA surveillance and decay pathways.

Main Methods:

  • Machine learning analysis to identify key features regulating mRNA decay.
  • Investigation of Upf1 binding to poorly translated and untranslated open reading frames (ORFs).

Main Results:

  • mRNA stability is combinatorially regulated by translation initiation strength, uORF content, codon optimality, AU-rich elements, microRNA binding sites, and ORF length.
  • ORF length was identified as the most critical conserved feature for mRNA decay.
  • Upf1 binds to poorly translated and untranslated ORFs, including those with uORFs and exposed ORFs post-termination.
  • Upf1 surveils mRNAs with exposed ORFs, long ORFs, ORF-like 3' UTRs, and uORFs.

Conclusions:

  • Upf1 plays a unifying role in surveilling poorly translated ORFs, contributing to mRNA stability and homeostasis.
  • A novel EJC-independent nonsense-mediated decay (NMD) pathway, termed ORF-mediated decay (OMD), is proposed, driven by Upf1's regulation of poorly/untranslated ORFs.