Feedback from the Nascent Chain Triggers Ribosomal Frameshifting and Transcript Decay

Carmody, P. J.; Sillman, C. R.; Dyotima,; Bhardwaj, R.; Farzam, A.; Golrokhmofrad, M.; Lewis, B. J.; Penn, W. D.; Drown, B. S.; Schlebach, J. P.

doi:10.64898/2025.12.23.696290

bioRxiv · 10.64898/2025.12.23.696290

Feedback from the Nascent Chain Triggers Ribosomal Frameshifting and Transcript Decay

Carmody, P. J.·Sillman, C. R.·Dyotima,·Bhardwaj, R.·Farzam, A.·Golrokhmofrad, M.·Lewis, B. J.·Penn, W. D.·Drown, B. S.·Schlebach, J. P.

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Abstract

Though ribosomes have several features that help them maintain their reading frame, these safeguards can be bypassed by RNA structures that promote -1 programmed ribosomal frameshifting (-1PRF). We recently found that conformational transitions in the nascent polypeptide can enhance -1PRF, though its unclear whether this feedback plays a general role in translational recoding. Here we demonstrate that the translocation of nascent transmembrane domains is sufficient to induce -1PRF during the decoding of slippery heptamers. We identify thousands of motifs that potentially trigger -1PRF along with proteomic identifications of 33 predicted human frameshift products. We also identify thousands of splicing-dependent motifs and demonstrate that the splicing-mediated reconfiguration of transmembrane domains alters -1PRF. Finally, we show that most transcripts bearing these motifs are sensitive to the nonsense-mediated decay regulator UPF1, suggesting they modulate mRNA turnover. Our findings show that the misassembly of growing polypeptides can trigger -1PRF, premature termination, and transcript decay.

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Carmody, P. J., Sillman, C. R., Dyotima,, Bhardwaj, R., Farzam, A., Golrokhmofrad, M., Lewis, B. J., Penn, W. D., Drown, B. S., Schlebach, J. P.. 2025-12-26. Feedback from the Nascent Chain Triggers Ribosomal Frameshifting and Transcript Decay. https://doi.org/10.64898/2025.12.23.696290

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