Scientists, including researchers from Poland, have explained the formation and functioning of an important structure, the so-called cap, which is part of the mRNA of trypanosomes. Their research may help create new strategies to fight these dangerous parasites of humans and cattle.
A publication presenting the results of research on the macromolecular complex involved in RNA metabolism in trypanosomes has been published in the journal Nature Communications. Explaining how it is formed and how it functions may allow to develop new therapies against these protozoa in the future. The co-authors of the publication include Polish researchers: Professor Jacek Jemielity and Kamil Ziemkiewicz from the Centre of New Technologies of the University of Warsaw, and Marcin Warmiński, PhD, from the Faculty of Physics of the University of Warsaw. In their research, they were accompanied by teams from Grenoble (France) and Innsbruck (Austria).
Trypanosoma is a family of parasitic protozoa that cause serious diseases in humans (e.g. African sleeping sickness, leishmaniasis) and farm animals. These diseases pose a serious threat to public health and cause large economic losses worldwide.
Trypanosomes stores genetic information in the form of DNA, but the way they read it and process it into mRNA differs from the mechanisms found in most eukaryotes. Their characteristic feature is an unusual 'cap' at the end of the mRNA.
Every cell - be it human, bacterial or protozoan - works thanks to the proteins that build it and regulate its functions. The instructions for their production are found in DNA, but in order to read it and produce a protein, the body creates an intermediate 'working copy', i.e. RNA. One form of RNA is mRNA (messenger RNA), which carries instructions from DNA to the 'protein factory' in the cell.
For mRNA to function properly, its ends must have special protective structures that prevent damage and help effectively translate information into protein. One such structure is the 'cap', located at the 5' end of the mRNA strand.
In most eukaryotic organisms, the 'cap' is basically identical, but in trypanosomes it takes on a form not seen anywhere else, which has been called cap-4. Compared to the standard 'cap', it contains more methyl groups, has a unique composition, and is added in the process called trans-splicing.
'It is a very characteristic feature of trypanosomes. This 5' end is the most heavily modified, if we take into account all the organisms examined in this respect. That is why this issue interested us so much. It was a very interesting synthetic challenge', says one of the authors of the study, Professor Jacek Jemielity, chemist, biochemist and director of the Centre of New Technologies at the University of Warsaw.
'Of course, we were also guided by the fact that trypanosomes can be very dangerous. They cause serious diseases in humans and cattle. Since trans-splicing occurs only in them and is necessary for the production of mRNA, it is crucial for their survival. A better understanding of its process, and consequently learning how to block it, could be useful in the context of developing new strategies to combat these protozoa', he adds.
Jemielity and colleagues obtained, in laboratory conditions, the structure of the 5' end of mRNA of one of the trypanosomes (Trypanosoma brucei) together with the accompanying CBC (Cap Binding Complex), responsible for important aspects of RNA metabolism, including the previously mentioned trans-splicing characteristic of these organisms.
The authors of the publication used cryo-electron microscopy to present the spatial structure of this macromolecular complex at the atomic level. They showed how its individual elements interacted with each other. In their opinion, this may help in future studies on mRNA maturation in these organisms.
As a result of their research, the scientists also discovered certain similarities and differences between the CBC complex in trypanosomes and its counterpart in mammals. This information is of key importance, because in the future it may help in the development of drugs against trypanosomes.
'This, of course, is only the beginning, but if it were possible to block the unique mechanism of the formation of the structure at the 5' end of mRNA in trypanosomes, it would be possible to potentially inhibit their multiplication in the host organism, without simultaneously damaging the host (human) cells. This, in turn, could be the basis for designing new therapeutic strategies against diseases caused by these parasites', Professor Jacek Jemielity points out.
'Time will tell whether this will lead to the development of new therapies against these protozoa in the future', he concludes.
PAP - Science in Poland, Katarzyna Czechowicz
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