Abstract
MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA-mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer –dependent and –independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation.
Highlights
MicroRNA, originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1,2,3]
The synthesis of miRNA by polymerase II (pol II) and polymerase III (pol III) implies that miRNA is a fundamental regulatory element generated from diverse loci within the human genome, which are involved in controlling gene expression essential for normal cellular function
A recent study suggests that RNA Helicase A (RHA), referred to as DHX9 or NDHll, is responsible for RNA duplex unwinding associated with RNA-induced silencing complex (RISC) activation in the human miRNA pathway [150]
Summary
MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1,2,3]. It is predicted that miRNA account for 15% of the human genome and regulate at least 30% of protein-coding genes [4,5,6,7,8]. This review will explore recent advances in human miRNA biogenesis and function to propose a working model of miRNA gene silencing It will examine miRNA involvement in cancer development and the medical implications. MiRNA precursors are commonly found in clusters through many different regions of the genome, most frequently within intergenic regions and introns of proteincoding genes These regions were referred to as “junk DNA” because their function was unknown. The synthesis of miRNA by pol II and pol III implies that miRNA is a fundamental regulatory element generated from diverse loci within the human genome, which are involved in controlling gene expression essential for normal cellular function. The first determinant is the origin of the miRNA, being either intergenic or coding-intronic [36, 82]
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