II transcription. In the nucleus, pri-miRNA is cleaved to a ~70 nucleotides stem-looped precursor (pre-miRNA) by the microprocessor complex. The core components of the complex are the RNase III Rnasen (Drosha) and its cofactor Dgcr8, essential for determining the cleavage site. The two RNase domains of the enzyme cleave the 5' and 3' single strands about 11 bp away from the junction of single- and double-stranded RNA. pre-miRNA is recognized by Xpo - a member of the nuclear transport receptor family which, in conjunction with GTP-bound Ran, transports it into the cytoplasm. The HEAT repeats of Xpo5 are important for both pre-miRNA and GTP-Ran binding. Hydrolysis of GTP to GDP in the cytoplasm leads to release of cargo. In the cytosol, pre-miRNA is processed by Dicer1 - the other RNase III in the pathway. Dicer1, aided by Tarbp2 (Trbp), cleaves the hairpin-loop of pre-miRNA to produce a ~22 nucleotide duplex. Binding of Tarbp2 to the helicase-like domain of Dicer induces conformational changes that abrogate its inhibitory effect. The relative thermodynamic stability of the base pairs at the ends of the duplex determines which strand will become the mature or guide strand. The strand with the less stable 5'end becomes the guide of the miRNA-induced silencing complex (RISC) - the effector complex of miRNA pathway. Members of the argonaute family of proteins are core components of RISC complex; its assembly however, is not well understood and appears to vary between species.  In mammals, four proteins of the AGO subfamily with redundant functions are involved in miRNA and siRNA pathways. The ~100kDa proteins contain characteristic PAZ, MID (middle) and PIWI domains; PAZ and MID contact the 3' and 5' end of miRNA, respectively. miRNAs and target mRNAs form partially complementary duplexes with the 5' 2-8 nucleotide 'seed' sequence of miRNA and the 3' UTR sequence of target mRNA. The mechanism of target gene translational repression is poorly understood. miRNA can also mediate destabilization of mRNA by inducing its deadenylation and subsequent degradation. Tnrc6 (GW182) proteins - the second component of RISC acting downstream of AGO, contact AGOs via the N-terminal GW repeats; the C-terminus contacts a poly A binding protein (PABP) which recruits deadenylases. miRNA are involved in the control of their own transcription by single- or double-negative (positive) feedback loops. Editing of RNA molecule also serves as control; deamination of adenosine to inosine can affect processing by either RNase with mostly negative consequences. Many other proteins fine-tune, up- or down-regulate the pathway. Aberrant expression of miRNAs has been observed for many conditions including various types of cancer. To see the ontology report for annotations, GViewer and download click here...(less)