Jingjing Zhou, PhD student in biochemistry

What diseases are you working on ?

They're quite diverse. The mechanism I'm studying lies at the center of a " crossroads   ": it will affect different aspects of our body. For example, it is linked to type diabetes 2, to rather rare genetic diseases such as acute infantile liver failure, or to Leigh syndrome, which is a progressive brain disorder. What these diseases have in common is a defect in the synthesis of the enzymes that modify transfer RNAs (tRNAs).

What role do these transfer RNAs play in the body's biological processes ?

RNAs play a key role in protein synthesis. Proteins are biological molecules made up of amino acids that are fundamental to the activity of the human body. They are like the workers of metabolism. They are also involved in the composition of skin, muscles, etc. Their functions are very broad : they are the basis of life.

To synthesize proteins, our body needs genetic information stored in the form of DNA. However, this information is not directly accessible by the body. For it to be used for protein synthesis, agents are needed to transmit this message (messenger RNA) and transfer amino acids according to the message's instructions . This is the role of transfer RNAs. It is for these reasons that I spoke of a " crossroads ".

Given the variety of their roles, RNAs are involved in the synthesis of different proteins that have different effects on the body. I'm working on transfer RNAs to understand how they work : how to ensure that genetic information can be correctly read before being transferred to instruct the synthesis of the required proteins. The diseases I mentioned are partly caused by the malfunctioning of these transfer tRNAs.

You work on the chemistry of the human body..

The field of chemistry in which I work is called biochemistry. Biology and chemistry are very closely linked. Although it's a vast discipline, for me chemistry is the study of the properties of matter down to the atomic scale and the effects of their interactions with each other. It is the various chemical reactions that enable the biological system to function. I work in Prof. Marc Fontecave's Chemistry of Biological Processes Laboratory in the RNA Modification Enzymes team, which focuses on these biochemical processes. For example, a transfer RNA is an assembly of carbon, nitrogen, oxygen and hydrogen atoms. For these molecules to be created, stabilized and functional, there are various chemical processes involved, such as sulfuration, which consists in the incorporation of sulfur into certain tRNAs.

It is this sulfuration process that constitutes your research focus ?

More specifically, I'm interested in the process of enzyme-catalyzed sulfuration. An enzyme is a protein that accelerates biochemical reactions, or catalyzes them. In the mechanism I'm studying, the enzyme enables sulfuration, i.e. the incorporation of sulfur atoms into RNA. But to be fully functional, these enzymes need what we call a " cofactor ". Without it, the reaction would be less efficient, if not impossible. This intermediary, metabolized by our bodies, is made up of four iron atoms and four sulfur atoms. It is known as the [4Fe-4S] center. It is essential for the enzyme's activity, and it may be a problem with the metabolism of this cofactor that affects patients suffering from the pathologies I mentioned. This is the focus of my research. This mechanism was already studied in the years 2000, but technical progress has now enabled us to pinpoint how it works.

How do you organize your day-to-day work ?

My work involves reproducing the tRNA maturation process. First of all, there's the cultivation of the bacteria I'll be working on. They are genetically modified to be able to synthesize the enzyme we need in large quantities. Then, I extract the proteins I'm interested in using a sonication process. Ultrasound projected by a probe creates a pressure that bursts the walls of the bacteria. After purification to eliminate undesirable proteins, everything takes place in a " glove box ". This is a chamber that isolates the proteins from the ambient air, where I then incorporate the cofactor [4Fe-4S] into the protein, as it is sensitive to oxygen and degrades on contact. The final step is to test the functioning of this assembled unit. To do this, I incubate the unmodified tRNAs with the enzyme I've just created in vitro , in the presence of the other necessary cofactors. If this enzyme unit is functional, there will be the presence of sulfur within the tRNA, which can be detected by various characterization techniques.
And of course... reading articles and talking with my thesis supervisor, Dr. Béatrice Golinelli, as well as with other researchers, are a real source of inspiration for moving forward with projects.

Can this research have a direct application ?

Some tRNA-related health problems are due to a deficiency in sulfur metabolism. For example, one of the only treatments currently available involves external supplementation with L-cysteine, the main sulfur donor in cells. This only alleviates symptoms, it's not curative. If we can understand how these mechanisms work at the molecular level, it could open the door to more effective treatments in the future. We could imagine reactivating sulphur tRNA synthesis in patients in whom it doesn't work. But all this is still a long way from practical application, and we're only at the basic research stage.

How did you become interested in these issues ?

Like many researchers, it was by chance. After my literary baccalaureate in China, I came to France. I wanted to learn French and discover European art. I settled in Reims, with the aim of studying oenology. You could say I was taken in by the wine culture that surrounded me ! These are highly technical studies, with a lot of emphasis on chemistry. That's how I got started in microbiology and biochemistry. During my bachelor's degree, we had a lecture on enzymology, which I really enjoyed because of its rationality. I was fascinated by the efficiency of natural enzymes compared with those produced by man. So I went on to study biochemistry, culminating in a Master's degree in Pharmaceutical Sciences, for which my 2 internship was with Dr Béatrice Golinelli at the Collège de France.

You recently defended your thesis. Are you thinking of continuing in research ?

I'd like to go into the pharmaceutical industry. Pharmacology is a field that relies heavily on the use of enzymes. I'm very interested in the practical side of research. What's more, in order to open myself up to the industrial world, I took a complementary training course during my third year of thesis, entitled " Business Foundations Certificate ". This is a collaborative program between the INSEAD business school and Sorbonne University. It's a very enriching experience, allowing me to meet people from different sectors and encouraging me to think about doing something that could really help, such as participating in the development of a treatment in a more concrete way than basic research. For me, that's the main benefit of research activities.

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Jingjing Zhou works under the supervision of Dr Béatrice Golinelli in the Molecular and Structural Enzymology team, within the Chemistry of Biological Processes Laboratory headed by Pr Marc Fontecave. Her thesis is entitled " Nouvelles fonctions des centers [4Fe-4S] dans des réactions non rédox : études bichimiques et structurales de thiouridylases d'ARN de transfert et d'une thiouracile désulfidase ".

Photos © Patrick Imbert
Interview by Aurèle Méthivier