Overview
microRNAs are small non-coding RNAs of 20 to 25 nucleotides in length that regulate expression of target genes through sequence specific hybridization to the 3' untranslated region (UTR) of messenger RNAs and either block translation or direct degradation of their target messenger RNAs. This novel class of RNAs was first discovered in C. elegans in 1993 by the laboratory of Dr. Victor Ambrose, and have now been identified in almost every species including the discovery of microRNAs in humans in 2000 by the laboratories of Dr. Gary Ruvkun and Dr. Thomas Tuschl.
microRNA genes are expressed in the nucleus of cells by RNA polymerase II as a long double stranded precursor called the primary microRNA, or pri-microRNA. The microRNA portion of the pri-microRNA transcript forms a hairpin with signals for double-stranded RNA specific nuclease cleavage. The double-stranded RNA specific ribonuclease Drosha processes the pri-microRNA to release the hairpin into a precursor microRNA, or pre-microRNA. The pre-microRNA is exported into the cytoplasm by a nuclear export protein termed Exportin 5. In the cytoplasm the pre-microRNA is cleaved by the enzyme Dicer into a 20 to 25 nucleotide long double-stranded RNA. The double-stranded RNA produced by Dicer are then separated. The single-stranded mature microRNA assembles into a protein-RNA complex called the RNA-induced silencing complex (RISC). Through the RISC complex the microRNA targets messenger RNAs by direct base pairing. The 5' region of a microRNA, known as the 'seed' region (nucleotides 1 through 8), is the most critical for targeting and function. The microRNA target sites are often imperfect matches and located in the 3' UTR of target messenger RNAs. Since microRNAs do not require perfect complementarity for target recognition, a single microRNA is able to regulate multiple messenger RNAs. Equally as important, the impact on each regulated messenger RNA is subtle, but the combined effect is significant and produces measurable phenotypic results.
microRNAs have been shown to play an integral role in numerous biological processes including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. Many microRNAs are conserved across multiple species indicating the evolutionary importance of these molecules as modulators of critical biological pathways. Indeed, microRNA expression or function is significantly altered in many disease states, including cancer, heart failure, and viral infections. Targeting pathways of human disease with microRNA-based drugs represents a potentially powerful new therapeutic approach.
