Demystifying the nuclear function of Argonaute proteins

The Argonaute family of proteins is highly evolutionarily conserved and plays essential roles in small RNA-mediated gene regulatory pathways and in a wide variety of cellular processes. They were initially discovered by genetics studies in plants and have been well characterized as key components of gene silencing pathways guided by small RNAs, a phenomenon known as RNA interference. Conventionally, guided by different classes of small RNAs, Argonautes bind to and silence homologous target sequences at the post-transcriptional level. Increasing lines of evidence support their multi-functional roles in the nucleus. Advances in high-throughput genome-wide methodologies have greatly facilitated our understanding of their functions in post-transcriptional gene silencing as well as in other nuclear events. In this point-of-view, we will summarize key findings from genome-wide analyses of the Ago subfamily of proteins in mammals and Drosophila, discuss their nuclear functions in the regulation of transcription and alternative splicing identified in recent years, and briefly touch upon their potential implications in cancer.