Regulation of microRNA processing in development, differentiation and cancer

Abstract

microRNA (miRNA) is a class of small, noncoding, regulatory RNAs. The approximately 21 nt mature miRNA is processed from larger precursor molecules following a coordinated series of events. In theory, miRNA processing may be regulated at any of these steps. A growing body of evidence has demonstrated various steps in the miRNA biogenesis process for which regulation occurs. RNA editing of miRNA precursors, SNPs or mutations in the miRNA precursors, regulation by RNA binding proteins, alterations in the levels of key processing proteins, as well as a number of unknown mechanisms contribute to the regulation of miRNA processing. This article reviews the available literature on the regulation of miRNA processing that occurs within normal cells, during development or in diseases such as cancer.

Fig 1

Biogenesis of miRNA and sites of regulation. miRNA is transcribed by RNA polymerase II to produce the primary precursor miRNA (I, pri-miRNA). The pri-miRNA is trimmed by Drosha/DGCR8 in the nucleus to produce the ∼ 70 nt precursor miRNA (II, pre-miRNA). The pre-miRNA is transported to the cytoplasm by Exportin 5 where it interacts with the RNAse III Dicer and TRBP/ Loquacious to produce the ∼ 21nt miRNA: miRNA* duplex (III). The miRNA strand (IV) is loaded into RNA-induced silencing complex (RISC) and the miRNA* strand is typically degraded. Possible sites of regulation include: A, A-I editing; B, SNPs or mutations; C, regulation of processing by miRNA-specific factors; D, altered levels of Drosha; E, altered levels of Dicer; F, sequestration into subcellular organelles.