The big role of small RNAs
The world's leading molecular biology laboratory has announced two discoveries made by biologists in the study of so-called small, or non-coding, RNAs. These molecules do not carry information about the structure of the protein, but they are associated with the most important processes in the life of both the cell and the whole organism.
As scientists from Cold Spring Harbor (USA) have shown, hereditary information can be transmitted with the help of small RNAs, and a new class of similar molecules has been discovered in metastatic cancers.
In order to explain the essence of these discoveries, it is necessary to turn to one of the most important processes in the life of a cell – protein synthesis. For a long time it was believed that DNA is primarily a carrier of information about the structure of a protein. On its matrix, RNA is synthesized (a molecule similar in structure to DNA, but not with a double, but with a single helix and a slightly different chemical composition), which is transferred from the nucleus to special protein synthesis complexes – ribosomes. There, a long protein molecule is assembled from individual amino acids. Thus, the DNA-RNA-protein chain has become a central postulate of molecular biology.
But after the discovery of the mechanism of protein synthesis in the 1970s, it was quickly proved that not all genes encode sequences of amino acids in proteins. They also synthesize RNA, which does not transfer information about future protein molecules to ribosomes. There are even more genes whose final product is RNA than there are genes encoding proteins.
In the work carried out on fruit flies, it turned out that one of these molecules can be inherited along with DNA molecules and is responsible for the ability to reproduce. A short chain of Piwi-RNA turned off the intracellular mechanism leading to the development of mutations in germ cells. (Piwi proteins are expressed by testicular cells, and a violation of their synthesis leads to the formation of defective sperm. A detailed analysis of individual Piwi protein molecules revealed "stuck" RNA chains to them, which eventually received the name "Piwi-interacting RNA" – Piwi-interacting RNA, piRNA).
Sterility or fertility (the ability to procreate) of fruit flies is determined not only by the information recorded in DNA, but also by the presence or absence of a short RNA molecule in the maternal egg. The results of the work of Gregor Hannon's group involved in the discovery of piRNA are published in the journal Science (An epigenetic role for materially inherited piRNAs in transposon silencing).
The molecule found by biologists blocks the work of transposons – mobile genetic elements capable of moving independently through the genome, embedding themselves in various sites. Such movements often lead to mutations, and, as a consequence, to disruption of the normal functioning of cells. Germ cells affected by such mutations cannot mature normally, and the body remains sterile. Biologist Barbara McClintock, who discovered transposons at the turn of the 1950s, later received the Nobel Prize, but many of the mechanisms regulating their activity still remained a mystery.
Short fragments of RNA, which are selectively synthesized only in the cells of the genitals, were discovered much later, in the 2000s. It has been shown that they are able to suppress the activity of transposons, and the authors of the article in Science took the next step by detecting the transmission of RNA through the maternal line to offspring. The offspring of drosophila (researchers are still cautious about other species, although the mechanism they found is quite universal) receives a molecular switch complete with DNA that suppresses the activity of certain genetic elements.
It should be noted that this expansion of hereditary information beyond DNA is not the first time. Chemical modification of the DNA molecule (for example, its methylation) or the proteins that make up the chromosomes, histones, can lead to the shutdown of genes. DNA molecules that are identical in their nucleotide sequence can give different combinations of traits due to a combination of "on" and "off" genes, and such an inheritance mechanism can also be called an extension of classical ideas about the transfer of genetic material.
Gregor Hannon, commenting on the results of the work, compares the discovery with the work of the immune system. The mother passes on to the offspring a set of antibodies – protein molecules that selectively bind to various foreign substances and help the immune system neutralize them. The transfer of an RNA molecule that binds to an undesirable element in its own genome and turns it off is a rather successful analogy, and now scientists are faced with the task of understanding where else such a mechanism can work.
RNA, which by itself does not carry information about the sequence of amino acids, can perform a variety of functions. The transport RNA carrying amino acids to the synthesized protein was predicted by Francis Crick (one of the founders of molecular biology), in the 1960s RNA was discovered as part of ribosomes - already in the central postulate, non–coding RNA was provided.
But in 1967, another assumption was made, confirmed at the turn of the 1980s (Sidney Altman and Thomas Ketch will receive the Nobel Prize for this discovery in 1989): since RNA, like protein, takes quite complex forms, it can also be a catalyst for chemical reactions. And if RNA can accelerate the course of chemical reactions, then the range of its capabilities is significantly expanded. RNA, for example, gets the opportunity to bind to various proteins, suppressing or, on the contrary, enhancing their enzymatic activity. Which, in turn, is able to influence the reading of information from other genes, thereby regulating the work of several different proteins at once.
Biologists who studied metastatic tumors in Cold Spring Harbor investigated the process of formation of non-coding RNAs, information about which is recorded in previously considered "junk" DNA fragments. Despite the fact that these parts of the genome do not encode any proteins, RNA molecules are synthesized from them, providing regulation of the synthesis of other proteins (Scientists at CSHL discover new RNA processing mechanism and a class of previously unknown small RNAs). In this case, the RNA that does not encode the protein is divided into two fragments with different functions. The discovery, which the researchers themselves call an important step in both fundamental biology and medicine, is described in the journal Nature.
The work was devoted to an RNA fragment with the code designation MALAT1, about which it is known that it does not encode a protein and is especially actively synthesized in cells of metastatic cancerous tumors. MALAT1, as it was established during the work, is split into two fragments: short and long. The short ones migrate from the nucleus to the cytoplasm, and the long ones accumulate in the nucleus. Scientists already knew about several different possibilities of non-coding RNA to participate in various processes, but in this case additional research was required, the result of which was the discovery of a new extensive class of previously unknown non-coding RNAs.
The role of the long fragment is still not fully understood. But understanding the mechanism of its work will help to find out new details of such an important process for medicine as the spread of cancer metastases.
The short fragment, according to the researchers, plays the role of an "interceptor": it binds to proteins that normally interact with transport RNA and participate in the synthesis of other proteins. If a small RNA discovered by scientists takes the place of a "legitimate" transport one, then this can lead to a change in the synthesis of not just one protein, but many different proteins at once.
The ability of a single molecule not only to massively change the nature of gene expression, but also to be transmitted independently of DNA by inheritance (by the way, there were indications of this before), means that such a molecule can play (and, as the works under discussion show, it does) no less important role than DNA itself. In practical terms, this provides very rich opportunities for controlling intracellular processes with high accuracy and at the fundamental level of the cellular genome.
While the synthesis of artificial RNA is too expensive for mass production of drugs, but the first experiments in this direction have already begun. Small fragments of RNA in cell culture have already suppressed the work of genes that cause sickle cell anemia, and theoretically this method can work for other diseases. And knowledge about the role of small RNAs in the inheritance of signs and the development of cancer will help to move faster from the first model experiments to applied medical research.
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of the "Tape"
03.12.2008