Widespread Influence of 3′-End Structures on Mammalian mRNA Processing and Stability

• Published in: Cell Vol. 169; no. 5; pp. 905 - 917.e11
• Main Authors: Wu, Xuebing, Bartel, David P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.05.2017
• Subjects: Base Sequence; Cell Line; cleavage and polyadenylation; CRISPR/Cas9; DMS-seq; high-throughput analysis; Humans; in vivo structural probing; mRNA 3′ end processing; mRNA stability; mRNA structure; Polyadenylation; RNA Folding; RNA metabolic labeling; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger - chemistry; RNA, Messenger - metabolism; RNA metabolic labeling; CRISPR/Cas9; in vivo structural probing; DMS-seq; cleavage and polyadenylation; high-throughput analysis; mRNA 3′ end processing; mRNA structure; mRNA stability
• ISSN: 0092-8674; 1097-4172
• 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. [Display omitted] •RNA structures facilitate cleavage and polyadenylation of thousands of human mRNAs•In cells, mRNA 3′-end regions are generally more folded than are other mRNA regions•Structures with stabilities resembling those of random sequences can be functional•More stable 3′-end structures enhance mRNA metabolic stability Folded structures near 3′ ends enhance both the maturation and the stability of many human mRNAs.