MicroRNA turnover and nuclear function

Once considered to solely function to modify gene expression by modulating mRNA stability, the repertoire of miRNA function has expanded to include not only cytoplasmic but also nuclear effects. While most miRNA biogenesis is canonical in which the initial cleavage of a primitive miRNA by the nuclear microprocessor complex yields a precursor miRNA (pre-miRNA), which undergoes Exportin-5/RanGTP-mediated nucleocytoplasmic shuttling followed by further processing into a mature miRNA, several noncanonical pathways of both synthesis and nucleocytoplasmic shuttling are now evident. This includes functionally mature miRNAs and components of the miRNA-induced silencing complex undergoing shuttling back into the nucleus to further modulate gene expression at the levels of both transcription and mRNA processing. In this chapter, we will review the process of miRNA biogenesis in light of key regulatory nuclear steps, the evidence supporting a nuclear role for mature miRNAs, and the mechanisms by which miRNA are degraded, thus terminating their activity.