Protein components of the microRNA pathway and human diseases

Abstract

MicroRNAs (miRNAs) are key regulators of messenger RNA (mRNA) translation known to be involved in a wide variety of cellular processes. In fact, their individual importance is reflected in the diseases that may arise upon the loss, mutation or dysfunction of specific miRNAs. It has been appreciated only recently that diseases may also develop when the protein components of the miRNA machinery itself are affected. The core enzymes of the major protein complexes involved in miRNA biogenesis and function, such as the ribonucleases III (RNases III) Drosha and Dicer as well as Argonaute 2 (Ago2), appear to be essential. However, the accessory proteins of the miRNA pathway, such as the DiGeorge syndrome critical region gene 8 (DGCR8) protein, Exportin-5 (Exp-5), TAR RNA binding protein (TRBP) and fragile X mental retardation protein (FMRP), are each related, in various ways, to specific genetic diseases.

Figure 1

Protein components of the microRNA-guided RNA silencing pathway and human diseases. Encoded by the genome, microRNA (miRNA) and messenger RNA (mRNA) genes are transcribed by RNA polymerase II in the nucleus. The primary miRNA (pri-miRNA) is recognized and cleaved by the Microprocessor complex, which contains Drosha and the DiGeorge syndrome critical region gene 8 (DGCR8) protein, to form the miRNA precursor (pre-miRNA). Following its export into the cytoplasm via Exportin-5 (Exp-5), in a Ran·GTP-dependent manner through the nuclear pore complex (NPC), the pre-miRNA is cleaved by the Dicer·TAR RNA binding protein (TRBP) complex into a miRNA-miRNA* duplex. This complex is then joined by Argonaute 2 (Ago2) to form a miRNA-containing ribonucleoprotein (miRNP) complex, after which the miRNA strand is selected. Depending on the degree of complementarity between the miRNA and its mRNA target, the miRNP complex will either (1) mediate mRNA cleavage if the complementarity is perfect, or (2) initially inhibit mRNA translation if the complementarity is imperfect. In this latter case, the repressed mRNA is translocated to the P-bodies, after which the mRNA can either be destroyed or relocalized to the translational machinery for expression upon a specific cellular signal.