11.11: MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA ends have been methylated to prevent degradation, it is exported from the nucleus into the cytoplasm.
In the cytoplasm, another endonuclease enzyme, called Dicer, cuts the pre-miRNA into a 21–24 nucleotide-long miRNA duplex. Then, Dicer cleaves one strand of the duplex, releasing a single strand of mature miRNA. The mature miRNA is loaded onto a protein complex called RNA-induced silencing complex (RISC), which the miRNA then guides to the complementary region of its target mRNA.
The extent of complementary base-pairing between miRNA and the 3' untranslated region of target mRNA determines the gene silencing mechanism. Extensive or near-perfect complementarity causes degradation of mRNA, whereas limited base-pairing inhibits translation. While silencing via mRNA degradation is irreversible, translation inhibition is reversible since stable mRNA can resume translation after elimination of the repressors.
Altered miRNA expression or function is observed in several types of cancers. For example, loss of let-7 miRNA is observed in lung, liver, breast, prostate, and ovarian cancer. Let-7 miRNA inhibits the expression of oncogenes—genes with the potential to cause cancer—that promote cell growth, survival, and proliferation. Therefore, loss of let-7 promotes tumor formation.
