Stimulation of pri-miR-18a Processing by hnRNP A1

Recent evidence suggests that the canonical miRNA processing pathway can be regulated by a number of positive and negative trans-acting factors. This chapter provides an overview of hnRNP Al-mediated regulation of miR-18a biogenesis. Our laboratory has recently established that the multifunctional RNA-binding protein hnRNP Al is required for the processing of miR-18a at the nuclear step of Drosha-mediated processing. By combining structural and functional analysis of RNA, we showed that hnRNP Al regulates the processing of pri-miR-18a by binding to its terminal loop and reshaping its stem-loop structure, thus allowing for a more effective Drosha cleavage. Furthermore, we linked the event of hnRNP A1-binding to the pri-miR-18a with an unusual phylogenetic sequence conservation of its terminal loop. Bioinformatic and mutational analysis revealed that a number of pri-miRNAs have highly conserved terminal loops, which are predicted to act as landing pads for trans-acting factors influencing miRNA processing. These results underscore a previously uncharacterized role for general RNA-binding proteins as factors that facilitate the processing of specific miRNAs, revealing an additional level of complexity for the regulation of miRNA production and function.