![]() It is therefore unsurprising that dysregulation of miRNA silencing has been implicated in several pathologies, including diabetes, cardiovascular disease, and various forms of cancer. The most evolutionarily conserved of these can be grouped into 87 miRNA families, which have predicted target sites in over half the protein-coding genes in the human transcriptome. Subsequently, over 2000 putative miRNAs have been identified in humans. In 1993, the first miRNA, lin-4, was discovered in Caenorhabditis elegans. MicroRNAs (miRNAs), which are typically 21–23 nt in length, regulate gene expression in eukaryotes and thereby participate in diverse physiological processes, including epithelial regeneration, cardiac development and function, ovulation, and neuronal plasticity. In this review, we reflect upon these advances from a structural perspective and look forward to the major open questions and challenges ahead. Great strides have been made towards understanding how different forms of Argonaute are programmed through the assembly of RISC, how Argonaute reshapes its RNA guide to enable target searches, how targets recognized by RISC are silenced, and how RISC itself is regulated. The past ten years have seen major advances in structural and mechanistic understanding of the Argonaute proteins. Silencing mechanisms used by RISC are diverse, as a variety of distinct silencing pathways have evolved around the central ability of Argonaute proteins to rapidly and efficiently identify target RNAs. RISC is also remarkably fast and fastidious in finding its targets, with the ability to identify targets at rates approaching the limit of diffusion while avoiding the off-targets that are highly abundant in the cellular milieu. RISC is versatile in silencing diverse genes because Argonaute can be loaded with a small guide RNA of essentially any sequence. Argonaute uses the sequence information encoded in the small RNA as a guide to identify complementary RNAs targeted for silencing. The functional core of RISC is composed of a small RNA loaded into a member of the Argonaute protein family. The result is a family of fully programmable and highly efficient molecular complexes capable of identifying and silencing essentially any gene. RISC combines the natural capacity of nucleic acids to store and convey complex sequence information with the ability of proteins to fold into highly functional and dynamic molecular machines. The wide-spread utility of small RNAs in biology arises from the remarkable molecular assemblies in which small RNAs function: the RNA-Induced Silencing Complexes (RISC). Since their discovery over 25 years ago, small RNAs (21–30 nt) have emerged as major regulators of gene expression in nearly all aspects of animal biology.
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