Feedback from the Nascent Chain Triggers Ribosomal Frameshifting and Transcript Decay.

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Ribosomes possess safeguards to maintain translational reading frame fidelity.
• Programmed ribosomal frameshifting (-1PRF) can bypass these safeguards, particularly -1PRF.
• Nascent polypeptide conformation's role in -1PRF is not fully understood.

Purpose of the Study:

• To investigate if nascent transmembrane domain translocation induces -1PRF.
• To identify motifs triggering -1PRF and associated frameshift products.
• To explore the link between splicing, transmembrane domains, -1PRF, and mRNA decay.

Main Methods:

• Experimental induction of -1PRF by nascent transmembrane domain translocation.
• Proteomic analysis to identify frameshift products.
• Analysis of splicing-dependent motifs and their effect on -1PRF.
• Assessment of mRNA decay sensitivity to UPF1.

Main Results:

• Transmembrane domain translocation is sufficient to induce -1PRF on slippery heptamers.
• Thousands of motifs potentially triggering -1PRF were identified, with 33 human frameshift products confirmed.
• Splicing-mediated changes in transmembrane domains alter -1PRF.
• Most identified transcripts are sensitive to UPF1, indicating modulation of mRNA turnover.

Conclusions:

• Polypeptide misassembly, including transmembrane domain formation, can trigger -1PRF.
• This mechanism links polypeptide synthesis errors to translational recoding and mRNA decay.
• Findings suggest a novel regulatory pathway involving nascent polypeptide structure, frameshifting, and mRNA stability.