RNA-based recognition and targeting: sowing the seeds of specificity

• Published in: Nature reviews. Molecular cell biology Vol. 18; no. 4; pp. 215 - 228
• Main Authors: Gorski, Stanislaw A., Vogel, Jörg, Doudna, Jennifer A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2017; Nature Publishing Group
• Subjects: 631/337/384/2053; 631/337/384/331; 631/535; Archaea; Bacteria - genetics; Base pairs; Biochemistry; Cancer Research; Cell Biology; Cellular control mechanisms; CRISPR; CRISPR-Cas Systems; Deoxyribonucleic acid; Developmental Biology; DNA; Eukaryotes; Gene Expression Regulation; Gene Silencing; Genetic aspects; Life Sciences; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Nucleic acids; Nucleotide sequence; Properties; Proteins; review-article; Ribonucleic acid; Ribonucleoproteins; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Seeds; Sequences; siRNA; Stem Cells; Target recognition
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm.2016.174

Key Points RNAs involved in gene regulation and genome defence need to identify their correct targets in the cell against a background of diverse RNA sequences. Several RNA-based systems have converged on a similar strategy to find their targets. They initially present only a small subregion of the RNA, called a 'seed sequence', to interrogate and specifically bind to their corresponding nucleic acid targets. Argonaute-bound guides present their seed sequence in a pre-organized A-form helix that is already in the correct configuration to bind the mRNA target. Cas9–CRISPR RNA (crRNA) also presents the crRNA seed region in an A-form helix to interrogate potential DNA targets. The Hfq-bound small RNA RydC presents its seed sequence in an extended configuration at the site in Hfq that is involved in its annealing activity. Two general principles have emerged: first, the seed sequence is presented in a conformation that facilitates the search for, and interaction with, target nucleic acids and second, target recognition and conformational changes are coupled within the ribonucleoprotein to ensure that the correct RNA or DNA is regulated. Insights into eukaryotic, bacterial and archaeal RNA-based regulatory systems, including microRNAs, small interfering RNAs, clustered regularly interspaced short palindromic repeats (CRISPR) RNA and small RNAs that are dependent on the RNA chaperone protein Hfq, have revealed that they achieve specificity using similar strategies. Specifically, the presentation of short 'seed sequences' within a ribonucleoprotein complex facilitates the search for and recognition of targets. RNA is involved in the regulation of multiple cellular processes, often by forming sequence-specific base pairs with cellular RNA or DNA targets that must be identified among the large number of nucleic acids in a cell. Several RNA-based regulatory systems in eukaryotes, bacteria and archaea, including microRNAs (miRNAs), small interfering RNAs (siRNAs), CRISPR RNAs (crRNAs) and small RNAs (sRNAs) that are dependent on the RNA chaperone protein Hfq, achieve specificity using similar strategies. Central to their function is the presentation of short 'seed sequences' within a ribonucleoprotein complex to facilitate the search for and recognition of targets.