Structure-mediated RNA decay by UPF1 and G3BP1

Post-transcriptional mechanisms regulate the stability and hence expression of coding and noncoding RNAs. Sequence-specific features within the 3’-untranslated region (3’UTR) often direct mRNAs for decay. Here we characterize a genome-wide RNA decay pathway that reduces the half-lives of mRNAs based on overall 3’UTR structure formed by base-pairing. The decay pathway is independent of specific single-stranded sequences, as regulation is maintained in both the original and reverse complement orientation. The regulation can be compromised by reducing overall structure through fusing the 3’UTR with an unstructured sequence. Mutating base-paired RNA regions can also compromise this structure-mediated regulation, which can be restored by re-introducing base-paired structures of different sequences. The decay pathway requires the double-stranded RNA-binding proteins UPF1, which is central for coordinating mRNA decay pathways, and its associated protein G3BP1. Depletion of either protein increased steady-state levels of mRNAs with highly-structured 3’UTRs as well as levels of highly-structured circular RNAs. This structure-dependent mechanism therefore enables cells to selectively regulate coding and noncoding RNAs.