McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Mol Cell. 2020 Apr 2;78(1):70-84.e6. doi: 10.1016/j.molcel.2020.01.021. Epub 2020 Feb 3.
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. Regulation can be compromised by reducing the overall structure by 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 RNA-binding protein UPF1 and its associated protein G3BP1. Depletion of either protein increased steady-state levels of mRNAs with highly structured 3' UTRs as well as highly structured circular RNAs. This structure-dependent mechanism therefore enables cells to selectively regulate coding and noncoding RNAs.
转录后机制调节编码和非编码 RNA 的稳定性，从而调节其表达。3'非翻译区 (3'UTR) 中的序列特异性特征通常指导 mRNA 降解。在这里，我们描述了一种基于整体 3'UTR 结构形成的碱基配对的全基因组 RNA 降解途径，该途径降低了 mRNA 的半衰期。该降解途径不依赖于特定的单链序列，因为在原始和反向互补方向上都能维持调节。通过将 3'UTR 与无结构序列融合来降低整体结构，可以破坏调节。也可以通过重新引入不同序列的碱基配对 RNA 结构来恢复这种结构介导的调节。该降解途径需要 RNA 结合蛋白 UPF1 及其相关蛋白 G3BP1。这两种蛋白的缺失均增加了具有高度结构化 3'UTR 和高度结构化环状 RNA 的 mRNA 的稳态水平。因此，这种结构依赖性机制使细胞能够选择性地调节编码和非编码 RNA。
