Identifying key steps in protein expression may promote the development of targeted drugs, which will not cause side effects
Right: Research student Liat Amir-Zilberstein and Prof. Rivka Dickstein.
Every living cell holds in its nucleus a cookbook containing detailed genetic recipes for the production of all the proteins necessary for the body. But in practice, different cells produce ("express") a different variety of proteins. In fact, no cell expresses the entire selection within it. The proteins are the main "actors" that activate the life processes in the body. A deficiency or excess of a certain protein, or changes in the activity level of the proteins, may lead to the development of various diseases. How, then, does the cell "know" these proteins to produce, and in what quantity? This is the question that preoccupies Prof. Rebecca Dickstein from the Department of Biological Chemistry at the Weizmann Institute of Science.
The protein production process begins with the formation of a messenger RNA molecule, which is a copy of the genetic code stored in DNA. This initial stage is called "copying". The messenger RNA transfers the genetic information to the ribosome - the cell's protein factory - which reads the "plan" and produces the required protein according to it. But when exactly - and why - does DNA "decide" to open its double helix and express itself, so that messenger RNA can be created from it? It turns out that this initial step, on the way to protein production, takes place when various regulatory proteins bind to the DNA and tell it to start the transcription process. Prof. Dickstein investigates the interrelationships between the regulatory proteins and the DNA.
One of the known regulatory proteins is called NF-kB. This protein is involved in a wide variety of basic biological processes such as inflammation, immune response, and "programmed" cell death. Disruptions in the activity of this protein lead to the development of various diseases, including autoimmune reactions and cancer. Therefore, developing ways to selectively affect its activity may help in the development of new drugs for these serious diseases. But the fact that this protein is essential for many different processes may mean that a drug that affects it will cause unwanted side effects. A new study by Prof. Dickstein may offer a way to circumvent this difficulty.
Most of the studies designed for this purpose focus on the first steps of the sequence of events activated by NF-kB, when it receives a signal that sends it into the cell nucleus. Prof. Dickstein, on the other hand, was interested in the end of the sequence of events, in the stage where the protein transmits its message to the DNA. At this stage, additional "players" are involved in the process. One of them is a DNA segment that functions as a sort of "genetic circuit breaker" that initiates the transcription process. In fact, there are two types of initiator genetic segments: those that include the TATA sequence of genetic letters, and those that do not. When a regulatory protein such as NF-kB tries to bind to the DNA and instruct it to start expressing itself, it must do so in coordination with the initiating genetic segment.
In a previous study, Prof. Dickstein and the members of her research group discovered that the regulation process continues even beyond the transcription initiation phase, and identified a protein that regulates the process of messenger RNA formation. In the current study, together with research student Liat Amir-Zilberstein, the members of the group discovered that only binding of NF-kB to a gene containing an initiating genetic segment that does not include the TATA letter sequence allows the regulatory protein to participate in the RNA formation phase. On the other hand, in genes that are regulated by NF-kB and contain an initiator genetic segment that includes the letters TATA - this protein does not participate in the regulation of the formation process of the messenger RNA (in this case the regulation of the formation of the messenger RNA is done by a protein Other). Thus it became clear, for the first time, that the stage of the beginning of transcription affects the more advanced stage of the process, in which messenger RNA is created.
In addition, the scientists discovered that there is a fundamental difference between genes whose expression is controlled by NF-kB, but which contain different types of genetic initiator segments. Genes that contain the TATA sequence work in certain types of cells only, and are responsible for the production of specialized proteins, such as those created during an inflammatory or immune response. On the other hand, genes whose starting genetic segment does not contain this sequence of letters, produce common proteins, which can be found in every cell and which are involved in general processes, such as cell division and the protein production process itself.
This discovery may pave the way for the development of drugs that will selectively affect only certain activities of NF-kB, without harming its other activities, which are essential for various processes, thus preventing broad side effects.
