MicroRNAs

MicroRNA (miRNA) is a small regulatory RNA approximately 22 nucleotides long that does not code for protein. Instead, it regulates gene expression by inhibiting messenger RNA (mRNA) translation into protein. MiRNA forms a complex with proteins called RISC (RNA-induced silencing complex), which binds to specific mRNA sequences through complementary base pairing, typically in the 3-prime untranslated region, silencing gene expression through mRNA cleavage or translation interference.

Mature miRNA is produced through sequential enzymatic processing. Primary miRNA (pri-miRNA) forms a stem-loop structure and is shortened by the Drosha enzyme into hairpin-shaped pre-miRNA within the nucleus. After methylation to prevent degradation, pre-miRNA is exported to the cytoplasm where the Dicer enzyme cleaves it into a 21-24 nucleotide miRNA duplex, then releases a single strand of mature miRNA ready for loading into RISC.

The extent of complementary base-pairing between miRNA and the 3-prime untranslated region of target mRNA determines the silencing mechanism. Extensive or near-perfect complementarity causes irreversible mRNA degradation. Limited base-pairing inhibits translation, which is reversible since stable mRNA can resume translation after repressors are eliminated.

Loss of let-7 miRNA is observed in lung, liver, breast, prostate, and ovarian cancers. Let-7 normally inhibits oncogenes—genes that promote cell growth, survival, and proliferation. When let-7 is lost, these oncogenes remain active, promoting tumor formation. Dysregulation of miRNA is correlated with potentially deadly diseases including cancer and heart disease.

MicroRNAs are transcribed from introns, which are non-coding regions within genes, or from intergenic regions, which are stretches of DNA located between genes. These genomic sources are processed through multiple enzymatic steps to produce biologically active mature miRNA that can regulate target mRNA molecules.

The RNA-induced silencing complex (RISC) is a protein complex that loads mature miRNA and guides it to complementary regions of target mRNA. Once bound through base-pairing interactions, RISC either facilitates mRNA degradation or blocks translation, depending on the degree of sequence complementarity. This mechanism represents an important type of post-transcriptional regulation in gene expression transcription splicing and translation.

After pre-miRNA is methylated at its ends to prevent degradation and exported from the nucleus into the cytoplasm, the Dicer enzyme cleaves it into a 21-24 nucleotide miRNA duplex. Dicer then separates one strand from the duplex, releasing the single-stranded mature miRNA that is subsequently loaded into the RISC complex for target mRNA recognition.