Over the last decade, a growing number of non-coding transcripts have been found to have roles in gene regulation and RNA processing. The most well known small non-coding RNAs are the miRNAs/miRs (microRNAs), which have been found to be involved in human tumorigenesis, revealing a new layer in the molecular architecture of cancer. Gene expression studies have shown that hundreds of miRNAs are deregulated in cancer cells, and functional studies have clarified that miRNAs are involved in all the molecular and biologic processes that drive tumorigenesis. miRNAs constitute a large class of phylogenetically conserved single-stranded RNA molecules of 19 to 25 nucleotides playing major role in post-transcriptional gene silencing by translational repression or mRNA cleavage (Ref. 1). Till date more than 500 miRNAs have been documented and the number is still growing. About 3% of human genes encode for miRNAs, and up to 30% of human protein coding genes are regulated by miRNAs (Ref. 2). Most miRNAs are transcribed by RNA Polymerase II as long pri-miRNAs (primary RNA) that contain a 5' CAP structure and a 3'polyadenylated tail. The pri-miRNAs are processed in the nucleus by the RNase III enzyme, Drosha, and the double-stranded- RNA-binding protein, Pasha (also known as DGCR8), into ~70-nucleotide pre-miRNAs, which fold into imperfect stem-loop structures. The pre-miRNAs are then exported into the cytoplasm by the RAN-GTP dependent transporter exportin 5 and undergo an additional processing step in which a double- stranded RNA of ~22 nucleotides in length, referred to as the miRNA:miRNA* duplex, is excised from the pre-miRNA hairpin by another RNAse III enzyme, Dicer, in association with its RNA binding partner TRBP. Subsequently, the miRNA:miRNA* duplex is incorporated into the miRISC (multiprotein RNA-induced silencing) complex, which includes the Argonaute proteins (Argonate2), where the passenger strand is removed and degraded and subsequently the mature miRNA guides the RISC to target mRNAs whose expression can be inhibited by translational repression through perfect or nearly perfect complementarity to 3' UTRs (Un-translated regions) or direct degradation of the target mRNA. It has been estimated that a single miRNA family can regulate as many as 200 different genes. Thus the effects of the miRNAs are pleotropic, and their aberrant expressions conceivably unbalance the cell¡¯s homeostasis, contributing to diseases, including cancer (Ref. 3 & 4).
References:
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