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Charles Jencks
?What is life? 2013
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vert bar The multitude of RNAs
The central dogma of molecular biology suggests that biological information is stored in DNA (Deoxy-ribonucleic acid) then flows via RNA (Ribonucleic acid) into proteins, which execute the functions dictated by DNA. DNA is a supreme data-storer - a molecule capable of storing millions of bytes of information and capable of making an exact copy of this information, so ensuring that every cell of an organism carries the full complement of inherited information.

RNA can also store genetic information, and uses the same 'language' as DNA, albeit changing one of the four nucleotides from Thymine to Uracil. RNA can also execute catalytic and regulatory functions, and in the right circumstances can even make copies of itself. Furthermore RNA is the only molecule capable of making protein, through messenger RNA (mRNA). Replication of DNA on the other hand involves various protein complexes including DNA polymerases. Without these proteins DNA cannot replicate itself, and without RNA, DNA cannot make protein.

RNA World hypothesis

We can surmise therefore that RNA may have been the first replicating molecule at the origin of life - the 'warm little pond' of Darwin. The RNA world theory proposes that an RNA-based life predated today’s DNA and proteins dominated cell metabolism. DNA is a later perfection of a molecular storage system in that it is the more stable (Mammoth DNA from 60,000 years ago is still 'readable').

RNA has an unprecedented structural flexibility and diversity. It is a dynamic molecule, which adopts a large variety of structures. Besides its catalytic abilities we now know that RNA interacts with DNA to switch genes on and off - it is the regulator of gene expression.

RNA is therefore no longer viewed as a passive carrier of genetic information, rather, it is appreciated as a structurally and functionally sophisticated molecule intimately involved in numerous key cellular processes.

The RNA world hypothesis is supported by the observation that many of the most critical components of cells (those that evolve the slowest) are composed mostly or entirely of RNA. This would mean that the RNA in modern cells is an evolutionary remnant of the RNA world that preceded ours.

Catalytic RNAs, ribozymes

The central machinery for protein synthesis, is the ribosome: a complex of ribosomal RNAs (rRNA) and numerous proteins. This large structure comprises 85% of all cellular RNA. Made of two sub-units, the ribosome links amino acids together in the order specified by the mRNA molecule. Once the ribosome finishes reading the mRNA molecule, the two sub-units split apart. The RNA in the ribosome acts as a catalyst in the assembly of the peptide 9protein) chain and is therefore termed a ribozyme.

A ribozyme (ribonucleic acid enzyme) is an RNA molecule that is capable of performing specific biochemical reactions, similar to the action of protein enzymes. The 1981 discovery of ribozymes demonstrated that RNA can be both genetic material (like DNA) and a biological catalyst (like protein enzymes), and contributed to the RNA world hypothesis, which suggests that RNA may have been important in the evolution of prebiotic self-replicating systems. Examples of ribozymes include the hammerhead ribozyme (right).

Regulatory RNAs

Messenger RNAs (mRNA) were recognised as the key link between DNA and proteins very early on in nucleic acid research. In recent years a greater understanding in how mRNA is edited after transcription has been further added to through numerous regulatory RNAs, such as microRNAs (miRNA). These short molecules (20-25 nucleotides) usually have perfect or near-perfect complimentary pairing with their messenger RNA targets and induce gene repression through degradation of their target mRNAs. The complexity of these pathways is only now being elucidated.

RNA interference (RNAi) also called post transcriptional gene silencing, is a biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules.

Two types of small RNA molecules – microRNA (miRNA) and small interfering RNA (siRNA) – are central to RNA interference. RNAs are the direct products of genes, and these small RNAs can bind to other specific mRNA molecules and either increase or decrease their activity, for example by preventing a mRNA from producing a protein. RNA interference has an important role in defending cells against parasitic nucleotide sequences – viruses and transposons – but also in directing development as well as gene expression in general.

The first miRNAs were characterized in the early 1990s, however, miRNAs were not recognized as a distinct class of biological regulators of genetic function until the early 2000s. Since then, miRNA research has revealed multiple roles in negative regulation by degrading mRNAs or suppressing translation, and even positive regulation by transcriptional and translational activation.

By affecting gene regulation, miRNAs are likely to be involved in most biological processes. Different sets of expressed miRNAs are found in different cell types and tissues. Aberrant expression of miRNAs has been implicated in numerous disease states, and miRNA-based therapies are under investigation.

Another regulatory group include Small interfering RNAs (siRNA), sometimes known as short interfering RNA or silencing RNA. These are a class of double-stranded RNA molecules, 20-25 base pairs in length. siRNA plays many roles, but its most notable is in the RNA interference (RNAi) pathway, where it interferes with the expression of specific genes with complementary nucleotide sequence. siRNA also acts in RNAi-related pathways, e.g., as an antiviral mechanism or in shaping the chromatin structure of a genome.

The past two decades have seen the discovery of a host of nonconformist RNAs. Small nucleolar RNAs (snoRNAs), for example, which can alter the nucleotides bases in other RNA molecules, or short hairpin RNA (shRNA) that can bind to mRNA, blocking translation, or cleaving and thus destroying the molecule.

Circular RNAs

The most recent discovery, in early 2013, reveals the importance of a previously enigmatic group of Circular RNAs (circRNAs). It has been found that these have the ability to specifically bind to micro RNAs, effectively silencing these regulator molecules. The molecules comprise “a hidden, parallel universe” of unexplored RNAs. Micro RNAs can suppress the translation of messenger RNA; while the circular RNAs can soak up the micro RNAs. The few accounts of circular RNAs in plants and animals were previously dismissed as genetic accidents or experimental artefacts, but once geneticists began to search for them they found literally thousands. Even more remarkable is the finding that many are made from the exons spliced out of mRNA molecules as they leave the nucleus.

The characteristic of homeostasis - literally staying the same, or standing still - enables gene control to be finely balanced at the molecular level in just the same way that the hormone insulin can balance blood sugar level, or even global climate can be mediated by the earth's biota under James Lovelock's Gaia hypothesis. There is clearly a highly complex and intrinsically beautifully balanced control of post-transcription gene control in all living cells. The great hope is that this opens up a vast landscape of practical gene therapies of enormous specificity.