Protein biosynthesis: made in Russia
RNA on a short leashTwo papers in the latest issue of Science are devoted to the study of the protein biosynthesis process, which is fundamentally important for the life of any cell.
It turned out that the mechanism placed on the pages of textbooks for a long time has not yet been fully understood by the scientists themselves. In particular, the reasons for the close relationship between the two main stages of the process – transcription and translation of DNA – were not known until recently.
Yevgeny Nudler, a professor at the University of New York and head of the GeronLab laboratory in Moscow, told about the study, which may soon get on the pages of encyclopedias.
Interviewed by Alexandra Borisova, "Газета.Ru ".
– What is the importance of the results obtained?– Let's start with the basics – the fact that everyone takes a general biology course in grades 10-11.
Information is encoded in DNA, that is, genes. And these genes, this information, must be converted into protein in the process of cell life. The transformation of the genetic code into protein takes place in two stages. The first stage is transcription, when the enzyme RNA polymerase takes a copy from DNA, synthesizing RNA (DNA has a double helix structure, and RNA has a single strand). RNA, in turn, serves as the matrix of the second stage – translation, which is carried out by ribosomes. At this stage, information from RNA is transcoded directly into protein, that is, ribosomes are a machine for protein synthesis.
Since the late 50s, it has been known that these two processes in bacteria are combined, combined in space. When RNA synthesis is underway (that is, RNA polymerase "travels" through DNA, even before the synthesis is complete), the ribosome already "sits" on the RNA and begins its synthesis. But that's almost all that was known. The functional side was not clear, it was not clear why it was necessary for these two processes to be connected.
What we found was a complete surprise. It turned out that the ribosome that "rides" behind the RNA polymerase controls the transcription process, that is, the speed at which the RNA polymerase "rides" through DNA.
This mechanism can be compared to the situation when the owner leads his dog on a tight leash. Instead of the dog pulling the owner, the latter pushes it forward. Moreover, the dog cannot escape because of the same leash.
A lot of very important conclusions follow from this fact. Since the ribosome controls the rate of transcription, these two processes are perfectly synchronized. This is important so that transcription does not go to waste: the cell does not need to synthesize RNA if it is useless, if protein biosynthesis cannot go further. If the RNA polymerase "escapes" from the ribosome, it will be stopped by another special protein – the termination factor. It tracks whether the ribosomes have stopped working. If he notices a pause, he "jumps" to the RNA polymerase and removes it from the DNA.
This mechanism is extremely important for the energy balance of the cell, for its stability. It is impossible to allow the energy-intensive process of transcription to be meaningless, fruitless. The bacterium is designed to save energy as much as possible. This gives it a chance to survive and compete with other bacteria, for example. There are always not enough nutrients, so everything is designed to optimally economically consume energy in the cell and adapt to certain environmental conditions.
We also explained the meaning, the reason why these two processes are so well synchronized. The ribosome is the main sensor of nutrients. When the cell is starving, this affects the efficiency of the ribosomes: the necessary substrates become scarce, and the ribosome works slower. For RNA polymerase, the number of substrates is mostly constant. Therefore, it is logical that it is the ribosome that controls the rate, and not the RNA polymerase. By definition, a ribosome cannot work faster than a polymerase, because it travels only along an already constructed RNA matrix. Therefore, nature very wisely gave the control functions to the ribosome.
To test our hypotheses, we conducted experiments to accelerate or slow down the work of ribosomes in different ways. For example, antibiotics can slow it down, and some mutations can noticeably accelerate it. Both lead to an ideal symbiotic and synchronous change in the rate of transcription. It also changes depending on the stage of growth: for example, if a cell begins to starve, then this affects the ribosome and polymerase.
In addition, we were able to explain how this synchronization is achieved at the molecular level. RNA polymerase oscillates at most sites as it moves through DNA. That is, immediately after moving forward, it slips back. This process is called "reverse motion": this movement is like on ice and occurs spontaneously. Because of this, her speed is less than it could be. One would think that something was wrong with her, that it was a flaw in her work. However, in fact, this is the deep meaning of the functioning of the system: this is how the process and speed of movement can be regulated. In fact, RNA polymerase hardly moves on its own. She tries to fly back, and only the ribosome, leading the subsequent protein synthesis "behind her back", pushes her forward. If the ribosome does not work, this mechanism also provides inhibition of RNA polymerase. RNA is located in a narrow channel of RNA polymerase: in it, like a thread through the eye of a needle, it is pulled back and forth. And if a certain "nodule" (ribosome) is sitting behind, the thread physically cannot move back – and the enzyme moves forward.
A few years ago, our group published a paper in Science on a similar topic. The RNA polymerase itself works by a similar mechanism. Usually, several RNA polymerase molecules travel along one DNA molecule at once - by steam train. The longer the "composition" is, the more actively the gene is expressed: they can go straight one after the other. Therefore, if one of the front molecules "stumbles", the back one does not let it fail and pushes it forward. Thus, there is a cooperative acceleration of movement: together they go faster.
Now we see that ribosomes can also carry out such acceleration. It turns out that the more active the gene, the better it will be transcribed and translated, the faster this process will go. Despite the high speed of reading DNA sections by RNA polymerase (tens of nucleotides per second), the overall speed is low, due to the fact that the gene molecules are very long, especially in eukaryotic cells. It takes minutes and even hours to count thousands and millions of nucleotides in a gene. And the faster the RNA polymerase goes, the faster the gene will be expressed.
– What is the possible practical application of your results?–Now we know that two key processes in gene expression – transcription and translation – are directly related physically, which was previously unknown.
If there is a connection, then there is also an opportunity to separate these processes in order to interrupt successful transcription. In the same issue, Science publishes a structural paper describing a possible bridge between RNA polymerase and ribosome. The authors claim that they are connected by a rigid bridge of two other proteins: one of them is associated with the ribosome, the other with RNA polymerase. For our part, we have started checking these results. If we can show that this bridge is really important and that its rupture can disrupt the synchronization of RNA polymerase and ribosomes, then this may be a new way to disrupt gene expression in bacteria. Based on this concept, new highly effective antibiotics can be developed – molecules that will break this bridge, that is, disrupt the normal expression of genes in bacteria.
– Tell us about the team of authors and the history of the work.– This work was mostly done in Russia.
As you can see, the first author of Sergey Proshkin's work has two places of work – New York and Moscow. He started this work in New York, in my laboratory, and then returned to Moscow. Thanks to the Dynasty Foundation, which gave me a grant and allowed me to establish a laboratory in Moscow, I was able to invite Sergey to work, and all further research was carried out there at the expense of the Dynasty Foundation.
I think this is a very good, very illustrative example of the fact that in Russia, with the right organization, it is possible to do science at the world level and publish the results in the most prestigious leading world journals.
This is the first article that came out of our Russian laboratory "GeronLab". However, this is not the only area of work. Several publications are in the process of being finalized, at different stages, and we hope that they will also be well received by the scientific community. The first swallow turned out to be very good.
Our laboratory is unique in its own way. In my opinion, this is the only such laboratory in Russia: it does not depend on any structures – neither from the Academy of Sciences, nor from universities. However, he closely cooperates with several scientific institutes in Moscow and St. Petersburg, primarily with the Research Institute of Genetics on the Warsaw Highway. Officially, it is registered as a non–profit organization and is called "GeronLab", because one of the main topics of work is the mechanisms of cell aging. We came to this laboratory with a number of topics that were started earlier, and this work is also a continuation of the old topic. Within the framework of Geronlab, funding came exclusively from the Dynasty Foundation, and this made it possible to organize such a unique enterprise.
Hopefully, we are showing by our example that if we just create good working conditions, then scientists like me, who have achieved something in the West, can organize productive groups in Russia, divide their time between working abroad and in their own country so that both sides will only benefit. For the scientists who have left, this is a wonderful chance to expand their opportunities, interests, and make new developments using talented and qualified specialists in Russia. In turn, young Russian scientists will not leave science or go abroad, but will continue to do their favorite thing in Russia with dignity and will learn how to do science at the international level.
Portal "Eternal youth" http://vechnayamolodost.ru28.04.2010