Wu Xuebing, Bartel David P
Howard Hughes Medical Institute and Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Howard Hughes Medical Institute and Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell. 2017 May 18;169(5):905-917.e11. doi: 10.1016/j.cell.2017.04.036.
The physiological relevance of structures within mammalian mRNAs has been elusive, as these mRNAs are less folded in cells than in vitro and have predicted secondary structures no more stable than those of random sequences. Here, we investigate the possibility that mRNA structures facilitate the 3'-end processing of thousands of human mRNAs by juxtaposing poly(A) signals (PASs) and cleavage sites that are otherwise too far apart. We find that RNA structures are predicted to be more prevalent within these extended 3'-end regions than within PAS-upstream regions and indeed are substantially more folded within cells, as determined by intracellular probing. Analyses of thousands of ectopically expressed variants demonstrate that this folding both enhances processing and increases mRNA metabolic stability. Even folds with predicted stabilities resembling those of random sequences can enhance processing. Structure-controlled processing can also regulate neighboring gene expression. Thus, RNA structure has widespread roles in mammalian mRNA biogenesis and metabolism.
哺乳动物mRNA内结构的生理相关性一直难以捉摸，因为这些mRNA在细胞内的折叠程度低于体外，且其预测的二级结构并不比随机序列的二级结构更稳定。在这里，我们研究了一种可能性，即mRNA结构通过将聚腺苷酸化信号（PAS）和切割位点并列在一起，促进了数千种人类mRNA的3'端加工，否则这些位点相距太远。我们发现，与PAS上游区域相比，RNA结构预计在这些延伸的3'端区域更为普遍，并且通过细胞内探测确定，其在细胞内的折叠程度确实更高。对数千种异位表达变体的分析表明，这种折叠既增强了加工过程，又提高了mRNA的代谢稳定性。即使是预测稳定性与随机序列相似的折叠也能增强加工过程。结构控制的加工还可以调节相邻基因的表达。因此，RNA结构在哺乳动物mRNA生物合成和代谢中具有广泛作用。
