By Merlin Crossley
Our genetic material is encoded in DNA (deoxyribonucleic acid).
DNA is famous. But you may also have also heard of RNA (ribonucleic acid). So, what is RNA, and what is it good for?
Quite a lot really. In fact, it is possible that early life used RNA as its genetic material and also used folded RNAs as chemical tools to survive. This is called the RNA world hypothesis.
RNA is similar to DNA in lots of ways. It is a long chain of sugars linked together by phosphate groups. There is a cyclic base attached to each sugar and the bases can pair with matching partners to make a double helix.
This resembles DNA but the helix is a bit contorted and often RNAs are folded into complex structures stabilised by short helices interspersed with long single-stranded loops.
The really important difference is that RNA has an extra oxygen molecule. This makes RNA less stable than DNA.
You might think that being unstable is a bad thing, but there are advantages. Organisms that need to change rapidly tend to use RNA as their genetic material. Viruses, such as influenza and HIV, choose RNA rather than the more stable alternative of DNA so they can change and keep one step ahead of the immune system of their hosts.
Many factors contribute to the high mutation rates in RNA viruses, including the instability of RNA and the poor proof reading activity in the enzymes that replicate RNA.
As well as serving as genetic material, RNA has another critical function in virtually all organisms: it acts as a messenger; a short-lived intermediate communicating the information contained in our genes to the rest of the cell.
Many genes need to be turned on in bursts. Think of a football fan shouting out at a key point in a game – we don’t want the message to last forever.
Genes do last a lifetime, so how do we provide short-lived messages?
We make RNA copies of our DNA genes. The messages, or mRNAs, reflect the sequence of bases in our DNA and travel out of the nucleus (where our DNA is stored) into the cytoplasm where they are translated into proteins. The proteins go on to do jobs in the cell and the unstable mRNAs simply decay or are degraded.
So RNA can act as a messenger in the process of ensuring genes are translated into proteins – the tools of the cell, things such as haemoglobin to carry oxygen round the body.
But how does this mysterious translation occur? Does it rely on chemical tools such as proteins?
It certainly does, but it seems that the proteins are not the key players. It is a remarkable fact that the really important players in triggering the chemical reactions to produce protein chains from the mRNA code are not other proteins, but specially folded RNA molecules – RNA enzymes or ribozymes.
The machinery for reading a protein from a messenger RNA is contained in a complex RNA enzyme and the functional parts are RNA molecules called ribosomal RNAs or rRNAs.
How come RNA can trigger chemical reactions but DNA doesn’t seem to? It is partly the extra oxygen and partly the special ability RNA has to fold up into complex shapes to form tools that can do things, whereas the double helix is regular and stable. The DNA double helix holds information securely but doesn’t do much else.
In 1989 Sidney Altman and Thomas Cech shared the Nobel Prize in Chemistry for demonstrating that RNAs could catalyze chemical reactions.
You might wonder how a chain of sugars and bases such as mRNA can even serve as a template for forming a protein chain. The answer is complicated but it involves some clever adaptors. Amazingly, those adaptors are also made of RNA, they’re called transfer RNAs or tRNAs. They use their cyclic bases to pair to their mirror images in the mRNA and line up the right amino acids to make the protein, while the rRNA triggers the reaction to do the joining.
The finding that absolutely essential functions such as encoding information, having a short-lived messenger to express it, and converting it into a set of functional protein tools, all involve RNA has led people to hypothesise that early life was made up of RNA.
In the beginning RNA possibly did the lot. But then gradually DNA took over as a more stable genetic material and proteins took over as more stable chemical tools. And RNA was gradually forgotten by some researchers, at least until recently.
Future of RNA
In 1998, American biologists Andy Fire and Craig Mello discovered RNA inhibition – how RNA can switch off genes.
We now know that a new class of small inhibitory RNAs (siRNAs which are about 20 residues long), fine tune the output from messenger RNAs. As mentioned RNA can form double strands – this allows siRNAs to bind messenger RNAs and interfere with their function.
These interfering RNAs are essentially “digital” inhibitors that are base for base mirror images of the messenger RNA. So it possible to make artificial inhibitors now. Thus a new industry has been born as researchers strive to turn genes off for experimental purposes and medical researchers investigate whether this can be used for therapies, such as turning off viruses or other harmful genes.
There has also been another interesting discovery – researchers have found that although only a small part of our genome encodes protein, around 2%, a much larger proportion is still copied into RNA.
The function of many of these long non-protein coding RNAs, called lncRNAs, is still being investigated but it seems that some act to catalyse chemical reactions and that others are involved in turning genes on or off either by binding messenger RNAs or by binding directly to the DNA genes they match.
If the world began with RNA then it is not really surprising that echoes of that RNA world remain and that RNAs are still involved in key life processes and are fundamentally important in gene regulation.
New classes of RNA molecules will continue to be discovered and it is seems likely that further insights into fundamental biology will emerge from this fertile ground in the future.
Merlin Crossley receives funding from the University of New South Wales, the Australian Research Council and the National Health and Medical Research Council.