The role of RNA in Biology

The Central Dogma of Molecular Biology, DNA is transcribed into mRNA, which is translated into a protein.

If you are a biologist, and especially a molecular biologist, then you know all about the Central Dogma and the role of RNA as the intermediate between DNA (coding for genes) and proteins (the final product of most genes).

There are a number of species of RNA, with messenger RNA (mRNA) being the product of transcription and is produced by RNA Polymerase (RNAP), while transfer RNA (tRNA) is used by the ribosome during translation as the mechanism for decoding the RNA sequence into a protein sequence and ribosomal RNA (rRNA) is a major constituent of the ribosome providing both structural form and enzymatic activity required for protein synthesis.

However, there are other types of RNA and perhaps one type that has become very well-known in recent years is small interfering RNA (siRNA). These short RNA sequences were first discovered (at the end of the 2oth Century -Hamilton & Baulcombe (1999). Science 286, 950-952) as molecules capable of silencing gene expression in plants. Closely related to SiRNA are MicroRNA (miRNA), these are also short (20+ nucleotides long) and occur in many copies within a genome, but are capable of regulating a large number of genes through a system involving the guidance of Argonaute proteins to silence specific genes. This led to them also being known as silencing RNAs and led to a massive expansion in interest in small RNA molecules and their potential for therapeutic and biotechnological uses is summarised in a recent paper (Glorioso, J.C. (2011). Gene Therapy (2011) 18, 1103).

The mechanism of action is that the small RNA molecules, which are released from a preMiRNA transcript of specific genes through a series of processing steps involving an exoribonuclease and export to the cytoplasm, bind specific pockets or folds within the Argonaute proteins and lead this protein to attach to specific mRNA and silence them, or mark them for destruction. Silencing is through binding of the MiRNA-Argonaute protein complex to the 5′-untranslated region (UTR) of the mRNA and only 6-8 complementary bases are required between MiRNA and mRNA for silencing to occur. mRNA destruction occurs by the Ago2, which is closely related to RNase H and the only Argonaute protein that retains this nuclease activity, but requires complete complementarity between the MiRNA and the UTR region of the mRNA.

MiRNA production is closely linked to specific cell types and various stages of cellular differentiation, while unexpected production of MiRNA molecules is linked to a number of disease states including cancer, diabetes, hearing loss and liver disease. Certain viruses (particularly from the Herpes virus family) produce a number of MiRNA molecules , which they use to overcome the human immune system by targeting the major Histocompatibility complex class I chain related molecule B (a natural killer cell ligand). Interference with these MiRNA molecules could enhance natural immunity to herpes viruses. Both increasing the levels of MiRNA in the cell and introduction of MiRNA molecules or their complements has been found to influence the development of diseases and the development of tumours (Broderick & Zamore (2011).  Gene Therapy 11, 1104-1110).  Clinical trials of MiRNA-complementary short oligonucleotides has already begun and this area promises a strong future research area.
I imagine over the next few years that the study of how short RNA molecules control gene expression and how they may effect disease development will show massive progress with a huge potential for new treatments (Kasinski & Slack (2011).  Nature Reviews Cancer 11, 849-864).