DECODE-PMD · Decoding Peptide-Mediated mRNA Decay: Uncovering the Role of Nascent Polypeptides in Gene Regulation

Cells tightly regulate mRNA stability to ensure accurate gene expression across diverse cellular states and conditions. Traditionally, selective mRNA degradation has been attributed to the recognition of nucleotide sequence elements by proteins or small RNAs that subsequently recruit decay factors. Conversely, an emerging mechanism termed “peptide-mediated mRNA decay” (PMD) involves the encoded protein: my postdoctoral work revealed how the nascent polypeptide—physically linked to the mRNA during translation by the ribosome—can direct mRNA decay. This process is exemplified by tubulin mRNAs, which are selectively degraded when cells sense excess free tubulin levels. In this novel type of regulation, a recognition factor binds the nascent polypeptide to recruit downstream factors that trigger mRNA degradation. Impaired tubulin PMD results in severe phenotypes like defects in cell division and neurodevelopment. Beyond tubulins, emerging evidence points to critical PMD mechanisms targeting transcripts encoding aggregation-prone proteins. I postulate that PMD represents an entirely unexplored paradigm of gene regulation that dynamically adjusts protein production to ensure cellular fitness. However, the mechanistic understanding of PMD is still limited and the full range of substrates remains unknown.In DECODE-PMD I will unravel how nascent polypeptides direct mRNA degradation on ribosomes and chart the transcriptome-wide map of PMD substrates. Specifically, I aim to (1) decode how mRNA translation and degradation are coupled during tubulin PMD using a biochemical reconstitution approach; (2) decipher the physiological triggers of tubulin PMD and its regulation; and (3) harness advanced sequencing methods to systematically identify PMD substrates and derive common mechanistic principles. Our innovative work will provide a conceptual framework for how cells exploit nascent polypeptide recognition for selective tuning of mRNA stability to maintain protein homeostasis.