Decoding Drug Abuse in Noncoding RNA?

The human genome comprises approximately 3 billion nucleotide (nt) bases and only 2% of them code genes that are translated directly into proteins. With the advancement of microarray technology, the completion of human genome sequencing, as well as the near completion of sequencing of several other vertebrate genomes, it is clear that a far greater number of genes transcribed into ribonucleic acids (RNAs) are not translated into proteins[1,2,3,4]. These so-called noncoding RNAs (ncRNAs) include ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and small nuclear RNAs (snRNAs). Several newly discovered families of ncRNAs include the 21-nt microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), small interfering RNAs (siRNAs), repeat-associated small interfering RNAs (rasiRNAs), and others[1,3,5]. Many ncRNAs are integrated into large complexes with proteins and likely other RNAs that lead to diverse biological reactions. With the exponential expansion of the list of newly discovered ncRNAs and ncRNA types, we are only at the beginning of understanding the function of ncRNA. However, emerging evidence suggests that at least one essential function of ncRNA is gene expression regulation, through, for example, RNA interference, gene silencing, DNA demethylation, chromatin remodeling, and gene activation[2,6,7,8,9]. X inactive specific transcript RNA (XIST RNA), for example, spreads in cis along the X chromosome and likely recruits gene silencing factors in the X chromosome[10,11]. In chromatin remodeling, transcription of HOTAIR, a 2.2-kb ncRNA, is found in HOXC locus, and represses HOXD locus in trans[9]. Perhaps the best-understood mechanism of ncRNA’s function in gene silencing is the role of miRNA. miRNAs are single-stranded, 18–25 nt, small ncRNAs. The primary transcript of miRNA is first excised by a double-stranded, RNA-specific endonuclease called Drosha into pre-miRNA. PremiRNA is then processed by another double-stranded RNA, Dicer. miRNA negatively regulate mRNA translation by forming a ribonucleoprotein complex, RNA-induced silencing complex (RISC), and by base-pairing, binds with the 3’-untranslated region (3’UTR) of target mRNAs. It is suggested that, depending on the miRNA identity, RISC can either suppress the mRNA translation or promote mRNA degradation on binding to the target mRNA[2]. Remarkably, due to the small size of miRNA and partial complementary binding for targeting requirements, one miRNA can regulate hundreds of mRNAs, and more than one-third of human genes may be regulated by miRNAs[12,13].