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Reproduction demystified

The identification of the nuclear region of Trypanosoma cruzi could well facilitate combating Chagas' disease

SERGIO SCHENKMAN/UNIFESPDetails of the nucleus of Trypanosoma cruzi: genes essential to reproduction group themselves in the red areaSERGIO SCHENKMAN/UNIFESP

Accustomed to being badly received over millions of years, the parasites of the Trypanosoma cruzi family, that cause Chagas’ disease, developed their own mechanisms of working that allowed them to escape from the defenses of the organisms that they invade and to reproduce swiftly. At the moment when they divide up and originate another identical cell, these protozoa do not follow the strategy of other organisms formed by cells with a nucleus. In the initial stage of protein production, instead of the decoding one gene at a time, the parasites of the Trypanosoma cruzi family read all of the genes at the one time. At this instant, the long spiraled DNA molecule, which contains the genes, spreads out along the periphery of the parasite’s nucleus. Only after this simultaneous copy of the genes finishes is it that the message of each gene is separated and the production of the proteins that are going to form their descendants begins.

Biologists from the Federal University of Sao Paulo (UNIFESP) have identified the region of the nucleus where hundreds of copies of a unique gene are concentrated, the SL (spliced leader) gene, essential for organizing this apparent disorder. And it is this gene that is going to mark, on each one of the other already copied genes, the starting point from which they must begin the production of proteins. The SL genes group themselves together in a very central region of the cell’s nucleus: the transcription factory of the SL gene. This discovery could create alternatives in the search for more efficient compounds to act against the protozoon that infects around 18 million people in Latin America. “If we manage to avoid this manufacturing factory of transcription forming, perhaps we can impede these parasites from reproducing”, says the biologist Sergio Schenkman, the group coordinator who unveiled the peculiarities of this protozoon family, which includes Trypanosoma brucei, which causes a type of sleeping sickness, and representatives of Leishmania genre, which brings about Leishmaniosis.

The special reproduction mechanism is very different from the classical workings of a cell – whether it be that of a human cell or one of a sponge. To a certain degree, a normal cell reminds one of a major city. Only that instead of cars and people moving along roads there are millions of structures that carry or interpret genes – as well as the proteins, sugars and fats molecules -, being transported all of the time to the outside or to the inside of the nucleus, for its part surrounded by a super populated space, the cytoplasm. The nucleus is equivalent to the mayor’s office and coordinates the activities continuously executed within the cell. It is from there that the commands that indicate when it is time to increase protein stock and to prepare for reproduction to come, and as well when it is time to rest and save energy.

Stored within the nucleus, the genes integrate into the extremely long molecule in the form of a spiral staircase – the deoxyribonucleic acid, DNA. The genes guard the cells commands as if they were law books archived in the city hall. As they are written in a very specific language, these commands are copied and interpreted before going forward, to be executed in the cytoplasm. During this process of copying and interpretation, known as transcription, each strip of DNA corresponding to a gene is read by enzymes and transformed into a molecule of genetically less complex material, the ribonucleic acid, or RNA. Among the almost ten forms of RNA already discovered, one is special – the messenger RNA – which passes through the membrane surrounding the nucleus and carries a simplified copy of this information to the ribosomes, the production units of proteins spread throughout the cytoplasm. This is what happens in the majority of living beings except for the protozoon family Trypanosomatidae.

It seems that up until now only these protozoa present a transcription factory of SL genes, described by the UNIFESP team in Eukaryotic Cell. This region of the nucleus is rich in polymerase II RNA, an enzyme capable of reading and interpreting the information contained in the SL gene. These enzymes generate an RNA molecule, created starting from the SL gene, the SL-RNA, which is going to adhere to one of the extremities of the copies of the other 22,500 genes of Trypanosoma cruzi, indicating that the production of the proteins in the cytoplasm can be initiated.

Intense transformation
Schenkman and his doctorate degree student Fernando de Macedo Dossin also showed that this factory is mounted each time that the parasite goes on to reproduce. In this phase its nucleus presents itself as an almost perfect sphere. Very close to the center of this sphere, the transcription factory for the SL gene assumes the configuration of a small globule and functions at full capacity. At the end of the reproductive period, the protozoon passes through an intense transformation in only three days and its nucleus becomes elongated. During this stage the parasite no longer reproduces, but it is then ready to invade mammals, and its transcription factory becomes less active with its components dispersed throughout the nucleus. Liberated in the feces of the Kissing Bug, the Trypanosoma arrives in the blood stream, penetrates into human cells and returns to its reproductive form.

Just like people who group together into a crowd, the transcription factory re-structures itself in the center of the nucleus and around 200 copies of the SL gene group together in an area rich in polymerase II RNA enzymes. For the parasite, it is more efficient to build this factory during the periods in which it needs to produce a lot and to deactivate it when the consumption falls. It is not known for certain why this occurs in the nucleus of this family of protozoon, but there are various hypotheses. Researcher Dossin believes that the concentration of polymerase II RNA in a specific region turns the transcription more efficient.

In a previous study, published in 2002 in Eukaryotic Cell,  Schenkman and Maria Carolina Elias had already observed another type of change in the nuclear structure of Trypanosoma cruzi. When the parasite assumes its reproductive form and initiates the transcription of the SL gene, the other genes migrate to the periphery of the nucleus, where they are copied. Only at the end of this reproductive period do the genes return to distribute themselves throughout the nucleus. For Schenkman, this is perhaps the mechanism through which the activity of the parasite’s genes is regulated.

During the last few decades, more powerful microscopes – capable of even producing 3-dimensional images of the interior of live cells – have allowed biologists to verify that the cell’s nucleus is so complex that it would leave the Scottish botanist Robert Brown, who described this cell structure for the first time in 1831, speechless.

Apparently there are well-defined regions of cells that, similar to workers districts in towns, group together RNA factories to which the genes direct themselves at the moment of transcription. Other regions, for their part, seem to serve as a depository for various compounds that move off towards the genes at the moment of cell duplication. The trafficking of the DNA, RNA and protein molecules in the interior of the nucleus is so intense that biologists and biochemists compare it to the movement – apparently chaotic – of people and railway carriages at the peak rush hours of a metro station. A detailed analysis, nonetheless, reveals that these movements are as precise as those of the mechanism of a Swiss watch.