microRNA (miRNA) elements are short (20-25 nucleotides (nt)), noncoding, single-stranded RNAs that bind to complementary sequences on target messenger RNA (mRNAs), which can result in translational repression or target mRNA degradation. microRNAs are critical components of developmental timing, responses to stress, and aging. Regulating the biogenesis and metabolism of miRNAs thus has an enormous impact on the health of the organism. In the genome, miRNAs reside in intergenic regions as well as within introns and exons of protein-coding genes. miRNAs are transcribed as long primary miRNAs (pri-miRNA). These pri-miRNA transcripts form hairpin-like structures with a double stranded stem and a terminal loop. pri-miRNAs are cleaved into smaller ~65-nt long precursor miRNA (pre-miRNA) by terminal-loop binding proteins and a microprocessor complex. This complex is composed of DRSH-1/DROSHA and PASH-1/DGCR8. In humans and yeast, the pre-miRNA product is exported to the cytoplasm by Exportin-5/XPO5 and RanGTP, respectively. The closest homologs of these proteins in C. elegans include xpo-1
and Y105E8A.1/yrs-2. Once in the cytoplasm, the pre-miRNA is cleaved at the top of the terminal loop by DCR-1/DICER, producing a duplex of two mature ~22nt miRNAs.An alternative, DRSH-1/DROSHA-independent, miRNA biogensis pathway has been identified in C. elegans and Drosophila. In this pathway pre-miRNAs are created through mRNA spliced introns. These introns form Mirtron lariats, which are debranched and refolded into pre-miRNA species. Mirtron generated pre-miRNAs are exported and processed in the same way as pre-miRNAs generated through the canonical miRNA biogenesis pathway. As mentioned previously, miRNA activity functions in many biological processes and hence needs to be temporally and spatially regulated. Much of that regulation occurs at the level of miRNA biogenesis and processing through Drosha binding/associated proteins, Dicer binding proteins, or proteins that bind to pri- and/or pre-miRNAs terminal loops. These regulators control expression or activity of miRNAs on specific miRNAs or families of miRNAs. For example, DCR-1 interaction proteins, ALG-1 and ALG-2, are required for lin-4
miRNA formation and maturation. miRNA processing can also be influenced by ADAR editing, cellular localization, proteins known to regulate transcription (such as p53
, SMADs) and proteins known to regulate mRNA stability (such as KSRP).