11.8: 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 into 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 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 repressors have been eliminated.

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.

MicroRNA, miRNA, is a type of small, regulatory RNA that does not code for protein. Instead it regulates gene expression by inhibiting the translation of messenger RNA, mRNA, into protein.

MicroRNAs are around 22 nucleotides long and are produced through the cleavage of a double-stranded RNA precursor molecule with a hairpin turn. The two strands separate, and one becomes the mature miRNA, which forms a complex with a group of proteins called RISC, RNA-induced silencing complex.

This complex binds to mRNA through complimentary base pairing between the miRNA and specific sequences in the mRNA, typically in the 3-prime untranslated region. This pairing is usually not perfect, but it is enough to inhibit translation, either through cleavage and destruction of the mRNA or by interfering with the translation process itself.

Either way, gene expression is silenced, which is an important type of post-transcriptional regulation. In fact, dysregulation of miRNA is correlated with potentially deadly diseases, such as cancer and heart disease.