Mechanisms of control of microRNA biogenesis

Abstract

MicroRNAs (miRNAs) are a class of ∼22 nt non-coding RNAs that control diverse biological functions in animals, plants and unicellular eukaryotes by promoting degradation or inhibition of translation of target mRNAs. miRNA expression is often tissue specific and developmentally regulated. Aberrant expression of miRNAs has been linked to developmental abnormalities and human diseases, including cancer and cardiovascular disorders. The recent identification of mechanisms of miRNA biogenesis regulation uncovers that various factors or growth factor signalling pathways control every step of the miRNA biogenesis pathway. Here, we review the mechanisms that control the regulation of miRNA biogenesis discovered in human cells. Further understanding of the mechanisms that control of miRNA biogenesis may allow the development of tools to modulate the expression of specific miRNAs, which is crucial for the development of novel therapies for human disorders derived from aberrant expression of miRNAs.

Fig. 1

miRNA biogenesis pathway. miRNAs are initially transcribed as a long, capped and polyadenylated pri-miRNA. The Drosha complex crops the pri-miRNA into a hairpin-shaped pre-miRNA. Next, Exportin-5 promotes the nuclear translocation of the pre-miRNA which is further processed by the Dicer complex. Following Dicing, the resulting miRNA : miRNA* is dissociated and the mature miRNA is incorporated into the RISC where it functions to mediate gene silencing either by translational inhibition or by promoting the degradation of target mRNAs.

Fig. 2

DEAD box RNA helicase-dependent miRNA processing pathways. The RNA helicases p68 and p72 play a critical role in the post-transcriptional regulation of numerous miRNAs in response to cellular signals, including TGF-β stimulation, DNA damage and estrogen stimulation. The downstream mediators of TGF-β stimulation and DNA damage, the Smads and p53, act to promote miRNA processing. Conversely, when bound to E2, ER-α reduces the processing of a subset of miRNAs. For clarity, some potential members of the Drosha processing complex are not shown.

Fig. 3

RNA helicase-independent mechanisms of miRNA processing regulation. (A) hnRNP A1 recognizes the terminal loop of miRNAs and promotes the structural remodelling of the stem region. Structural rearrangement generates a favourable Drosha-binding site and enhances pri- to pre-miRNA processing. NF90 and NF40 are strongly associated with the stem region of pri-miRNAs, which precludes association with the Drosha processing complex and thus inhibits the processing of miRNAs. (B) Similarly to hnRNP A1, KSRP binds to the loop region of miRNAs and promotes both the Drosha and Dicer processing. (C) Binding of Lin28 to the terminal loop prevents the association of both Drosha and Dicer with the pri- and pre-miRNAs, respectively. Additionally, Lin28 acts as a scaffold to promote the association of TUT4 with the pre-miRNA. TUT4 promotes the 3′-uridinylation of pre-miRNA which is then rapidly degraded.