Discovered in the early 90s of the 20th century, small RNA molecules turned out to be one of the fundamental mechanisms for regulating genetic activity.
It is necessary to immediately clarify that this does not just mean small RNAs, but a separate class of them called microregulatory RNAs, or microRNAs. They regulate gene activity, but how exactly? Here we need to remember why this regulation is needed at all. In every single organism, be it a human, a mouse, a fly, or a roundworm, all the cells in the body have the same genes and the same gene variants. That is, the DNA in the muscle cell will be the same as in the pancreatic cell. In fact, there may be some slight differences in the sequence due to copying errors during cell division. But these differences are really small, they do not give rise to any new variants (alleles) of genes, and, for example, the insulin gene in a muscle cell will be the same as in a glandular cell. With all this, the cells of different tissues and organs differ from each other. The differences between them are laid down during embryonic development and are maintained throughout life. This happens because different genes are active in different cells. In addition, our living conditions change here and there, and we need to somehow correspond to the changing environment. In order for this to happen, mechanisms are needed that stimulate the work of some genes and suppress the work of others.
When we say that a gene is active, we mean that information from it is copied by special molecular machines into RNA molecules. Further, other molecular machines that synthesize protein work with RNA molecules – they assemble it in accordance with the nucleotide sequences that RNA (more precisely, messenger RNA) brought from genes. The synthesis of RNA on DNA is called transcription, the synthesis of protein on messenger RNA is called translation. Back in the 1960s, proteins were discovered that control transcription on certain genes – these proteins were called transcription factors. There are a lot of them, they manage different genes and groups of genes, and depending on their behavior, the gene will be either transcriptionally active, or transcriptionally inactive, or inactive at all – that is, a lot of RNA will be synthesized on it, not very much, little or not at all will be synthesized.
In the late 1980s, Victor Ambros (Victor Ambrose) and Gary Ravkan (Gary Ruvkun), two current laureates, drew attention to some oddities in the individual development of the roundworm Caenorhabditis elegans. In worms with certain mutations in two genes, lin-4 and lin-14there were anomalies due to the fact that some groups of genes were not turned on in time. It was known that it was normal lin-4 suppresses activity lin-14. Gen lin-14 encodes a protein, and long messenger RNA is synthesized on it. If we were talking about transcriptional regulation, one would expect that in the gene lin-4
encodes a protein that suppresses transcription on lin-14.
However, Victor Ambros and his colleagues discovered that lin-4 A very short RNA is synthesized, which does not carry any protein information. And Gary Ravkan found out that lin-4 does not in any way affect the amount of messenger RNA that comes from lin-14. That is, the gene lin-4 suppresses a gene lin-14 anywhere, but not at the transcription stage. As a result, it turned out that this short RNA lin-4 binds to the long template RNA lin-14 and thereby prevents the synthesis of the protein that is encoded in the lin-14 RNA. In 1993, in two articles in Cell
A new mechanism for the regulation of genetic activity using microregulatory RNA (microRNA) lin-4 has been described – a post-transcriptional mechanism, because it occurs after the transcription stage (and at the same time blocks the translation stage).
Mechanism of action of microRNA: microRNA is synthesized on the lin-4 gene, which binds to messenger RNA from the lin-14 gene, blocking the functioning of the protein synthesizing apparatus. (Illustration: The Nobel Committee for Physiology or Medicine. Ill. Mattias Karlén)
The general scientific community initially perceived the new results as some kind of incident related only to roundworms. But by 2000, Gary Ravkan and his colleagues described the let-7 microRNA. The gene that codes for let-7 is extremely conserved and can be found in many, many animals, including humans. Due to the conservation of the gene let-7
the idea naturally appeared that in all animals that have it, it performs similar functions, that is, the mechanism with microRNA works in humans too. Attitudes towards microRNAs have changed. They began to be actively studied, there are already hundreds of them, and this is not the limit, because there are many sequences in DNA that look as if they encode microRNAs. They began to be discovered in a wide variety of living things, and over time it became clear that gene regulation by microRNAs is a fundamental mechanism common at least among all metazoans. Much has also become clear about what happens between microRNAs and the RNAs they regulate: in some cases, microRNAs stimulate the rapid destruction of messenger RNAs, in other cases they prevent the protein-synthesizing apparatus from working with them.
We hear about microRNAs regularly – they are needed not only for normal development, but also to keep cells in a normal, healthy state. We wrote that microRNAs help maintain the circadian rhythm in seasonal changes, that cancer cells use them to adjust metabolism in their favor, that they can be used in biotechnology and in the development of new drugs, in particular against the same cancer; and this is only a tiny part of the mass of studies devoted to microRNAs. At the very beginning we said that there are other small RNAs with special functions; Some of those other small RNAs were also awarded a Nobel Prize at one time. It is worth talking at least briefly about the features and differences of different small RNAs from each other, but we will still leave this topic for a journal article.
Gary Ravkan (left) and Victor Ambrose. (Photo by Ruvkun Lab, Wikimedia)
Source: www.nkj.ru
