XPO5 is required for miRNA biogenesis and promotes primary miRNA processing independent of RanGTP

XPO5 mediates nuclear export of miRNA hairpin precursors in a RanGTP-dependent manner. However, the requirement of XPO5 for global miRNA biogenesis and mammalian development and XPO5-associated RNA species are not determined. Here we show that XPO5 is required for mouse embryonic development and morphogenesis of skin and brain. Loss of XPO5 compromises the biogenesis of most miRNAs and that leads to severe developmental defects. Surprisingly, XPO5 not only associates with miRNA hairpin precursors but also pervasively binds to double-stranded RNA (dsRNA) regions found in many cellular RNAs and some clustered pri-miRNAs. The binding of XPO5 to miR-17~92 pri-miRNAs is RanGTP-independent. Pre-incubation with XPO5 enhances the processing efficiency of the DROSHA/DGCR8 microprocessor. Together, our studies demonstrate the requirement of XPO5 for miRNA biogenesis and mouse development, reveal an unexpected role of XPO5 for recognizing and facilitating the nuclear cleavage of clustered pri-miRNAs and identify numerous cellular RNAs as novel XPO5 subtracts. Overall design: Examination of RNA substrates of XPO5 in HEK293FT cells