UPF1 regulates mRNA stability by sensing poorly translated coding sequences
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 elemen...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-04-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724004029 |
| _version_ | 1827281392686333952 |
|---|---|
| author | Damir Musaev Mario Abdelmessih Charles E. Vejnar Valeria Yartseva Linnea A. Weiss Ethan C. Strayer Carter M. Takacs Antonio J. Giraldez |
| author_facet | Damir Musaev Mario Abdelmessih Charles E. Vejnar Valeria Yartseva Linnea A. Weiss Ethan C. Strayer Carter M. Takacs Antonio J. Giraldez |
| author_sort | Damir Musaev |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-04-24T08:59:53Z |
| format | Article |
| id | doaj.art-9b7151934acd4ab0a109531d0bef5848 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-24T08:59:53Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9b7151934acd4ab0a109531d0bef58482024-04-16T04:09:37ZengElsevierCell Reports2211-12472024-04-01434114074UPF1 regulates mRNA stability by sensing poorly translated coding sequencesDamir Musaev0Mario Abdelmessih1Charles E. Vejnar2Valeria Yartseva3Linnea A. Weiss4Ethan C. Strayer5Carter M. Takacs6Antonio J. Giraldez7Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USADepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; AstraZeneca, Waltham, MA 02451, USADepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510, USADepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Kenai Therapeutics, San Diego, CA, USADepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510, USADepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510, USADepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; University of New Haven, West Haven, CT 06516, USADepartment 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 authorSummary: 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).http://www.sciencedirect.com/science/article/pii/S2211124724004029CP: Molecular biology |
| spellingShingle | Damir Musaev Mario Abdelmessih Charles E. Vejnar Valeria Yartseva Linnea A. Weiss Ethan C. Strayer Carter M. Takacs Antonio J. Giraldez UPF1 regulates mRNA stability by sensing poorly translated coding sequences Cell Reports CP: Molecular biology |
| title | UPF1 regulates mRNA stability by sensing poorly translated coding sequences |
| title_full | UPF1 regulates mRNA stability by sensing poorly translated coding sequences |
| title_fullStr | UPF1 regulates mRNA stability by sensing poorly translated coding sequences |
| title_full_unstemmed | UPF1 regulates mRNA stability by sensing poorly translated coding sequences |
| title_short | UPF1 regulates mRNA stability by sensing poorly translated coding sequences |
| title_sort | upf1 regulates mrna stability by sensing poorly translated coding sequences |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724004029 |
| work_keys_str_mv | AT damirmusaev upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT marioabdelmessih upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT charlesevejnar upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT valeriayartseva upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT linneaaweiss upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT ethancstrayer upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT cartermtakacs upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences AT antoniojgiraldez upf1regulatesmrnastabilitybysensingpoorlytranslatedcodingsequences |