UPF1 regulates mRNA stability by sensing poorly translated coding sequences
Damir Musaev,
Mario Abdelmessih,
Charles E. Vejnar,
Valeria Yartseva,
Linnea A. Weiss,
Ethan C. Strayer,
Carter M. Takacs,
Antonio J. Giraldez
Affiliations
Damir Musaev
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
Mario Abdelmessih
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; AstraZeneca, Waltham, MA 02451, USA
Charles E. Vejnar
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
Valeria Yartseva
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Kenai Therapeutics, San Diego, CA, USA
Linnea A. Weiss
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
Ethan C. Strayer
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
Carter M. Takacs
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; University of New Haven, West Haven, CT 06516, USA
Antonio J. Giraldez
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Corresponding author
Summary: Post-transcriptional mRNA regulation shapes gene expression, yet how cis-elements and mRNA translation interface to regulate mRNA stability is poorly understood. We find that the strength of translation initiation, upstream open reading frame (uORF) content, codon optimality, AU-rich elements, microRNA binding sites, and open reading frame (ORF) length function combinatorially to regulate mRNA stability. Machine-learning analysis identifies ORF length as the most important conserved feature regulating mRNA decay. We find that Upf1 binds poorly translated and untranslated ORFs, which are associated with a higher decay rate, including mRNAs with uORFs and those with exposed ORFs after stop codons. Our study emphasizes Upf1’s converging role in surveilling mRNAs with exposed ORFs that are poorly translated, such as mRNAs with long ORFs, ORF-like 3′ UTRs, and mRNAs containing uORFs. We propose that Upf1 regulation of poorly/untranslated ORFs provides a unifying mechanism of surveillance in regulating mRNA stability and homeostasis in an exon-junction complex (EJC)-independent nonsense-mediated decay (NMD) pathway that we term ORF-mediated decay (OMD).
