Signaling-mediated regulation of MicroRNA processing

Abstract

miRNAs are important regulatory elements for gene expression that are involved in diverse physiologic and pathologic processes. Canonical miRNA biogenesis consists of a two-step processing, from primary transcripts (pri-miRNA) to precursor miRNAs (pre-miRNA) mediated by Drosha in the nucleus and from pre-miRNAs to mature miRNAs mediated by Dicer in the cytoplasm. Various routes of miRNA maturation that are tightly regulated by signaling cascades and specific to an individual or a subclass of miRNAs have been recently identified. Here, we review the current findings in signaling-mediated miRNA processing as well as their potential clinical relevance in cancer.

Figure 1. Canonical linear processing and alternative routes of miRNA maturation

A. Regulatory factors involved in nuclear miRNA processing are summarized as indicated. Mediator, direct interacting partner; E-X, enhancing factor-X; R-X, reducing factor-X. B. The direct upstream regulators for miRNA shuttling have not yet been identified. However, the XPO5 function is compromised in human primary colorectal tumors with microsatellite instability due to frameshift mutations. C. TRBP is phosphorylated and stabilized by activated MAPK-ERK pathway. Phosphorylated TRBP stabilizes Dicer and enhances general miRNA processing with the exception of pre-let-7, which is inhibited by TRBP phosphorylation. D. Lin28 recognizes and binds to the loop of pre-let-7 and subsequently recruits TUT4 and/or TUTase7 to uridylate the miRNA precursor at the 3’ terminus. Polyuridylation inhibits Dicer cleavage and tags the precursor RNA for rapid degradation by nucleases. E. KSRP interacts with Dicer and facilitates miRNA processing by recognizing and anchoring to the conserved region of precursor terminal loop. F. The loop structure of pre-miRNAs is also recognized by MCPIP1, a Dicer antagonist, which binds to and cleaves the loops from precursors for degradation. G. Ago2 is stabilized and functionally potentiated by hydroxylation at P700 mediated by type I collagen hydroxylase whose expression level is elevated under hypoxia. H. In response to hypoxia, Ago2 is phosphorylated by internalized EGFR at Y393 due to enhanced EGFR-Ago2 association in MVBs. Phosphorylation of Ago2 decreases its binding to Dicer, which then suppresses the maturation of a subclass of miRNAs with long-loop structures in their precursors. This in turn reduces the RISC activity due to a decreased loading of mature miRNAs onto RISC under hypoxia. EE, early endosome; MVB, multivesicular body.