A UPF1 variant drives conditional remodeling of nonsense-mediated mRNA decay release_2do4jed5rvaevgbys4bh52fsdq

Abstract

The nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Due to the major role of NMD in RNA quality control and gene expression regulation, it is important to understand how the pathway responds to changing cellular conditions. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1<jats:sub>LL</jats:sub>, enables condition-dependent remodeling of NMD specificity. UPF1<jats:sub>LL</jats:sub> associates more stably with potential NMD target mRNAs than the major UPF1<jats:sub>SL</jats:sub> isoform, expanding the scope of NMD to include many transcripts normally immune to the pathway. Unexpectedly, the enhanced persistence of UPF1<jats:sub>LL</jats:sub> on mRNAs supports induction of NMD in response to rare translation termination events. Thus, while canonical NMD is abolished by translational repression, UPF1<jats:sub>LL</jats:sub> activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.
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