When writing an email, it's all too easy to click the "send" button before we read it one more time. Then you regret the embarrassing mistake that was forgotten and sent. But when sending genetic messages in a cell, you must not give up the proofreading. In such a case, the mistakes may cause not only embarrassment, but also cancer or other diseases.
An important proofreading process for protein production takes place in the cell nucleus at the messenger RNA stage - the molecule that "transports" the production instructions from the nucleus to the protein production machinery. After the instructions found in the genes are transcribed into primary messenger RNA molecules, they go through a process called "splicing": segments of the genetic code are derived and reconnected to each other, sometimes in several different ways, to obtain the final molecule. As a result of this process, it is possible to "write" different messages based on the same initial genetic sequence.
Various findings indicate that the splicing process is more complex than simple cutting and gluing of different segments. Prof. Yosef Sperling and Dr. Eyal Kimchi from the Department of Organic Chemistry in the Faculty of Chemistry at the Institute, together with Prof. Ruth Sperling and Dr. Oleg Reitskin from the Hebrew University of Jerusalem, noticed that certain sections do not always make it into the final version, even though they are marked with clear signs as suitable for inclusion. There is a good reason for this: these segments carry a "stop" code - three genetic bases that signal the end of protein production. Inserting a messenger RNA carrying the code in the wrong position into the protein production machines (ribosomes) can cause the production of defective proteins, thus disrupting important biological processes.
The splicing mechanism knows that it must skip the sections that carry the "stop" code, and go to the following sections. But how exactly does he know this? The Sperlings and their research teams studied this proofreading process. Their findings, which recently appeared in the Journal of the National Academy of Sciences of the USA (PNAS), challenge the conventional way of thinking about the way in which genes are translated into proteins. According to their findings, proofreading is done by a certain RNA molecule called "transfer-primer-RNA". This small molecule is already known to scientists as having an essential role in the process of protein production in the ribosome: there, an RNA-initiator reads the "start" code at the beginning of the sequence of instructions in the RNA-messenger, and gives the command to start producing the protein. The new study shows that initiator RNA molecules enter the picture at a much earlier stage than previously thought - already at the time when the initial copies of messenger RNA undergo the splicing process in the cell nucleus. As in the protein production process, in this case too they receive the signal to act from the "start" code in the genetic sequence. But in the process of splicing, it seems that the primer RNA also looks for the "stop" instruction code, causing the splicing mechanism to not include these segments in Bar-en-Shilik. To test this, the scientists created artificial genetic sequences that contained mutated "start" codes - so that the RNA primer could not read them. In this case, even segments that contained "stop" codes survived the splicing stage. Later, the scientists added a correspondingly mutated primer RNA so that it could read the messed-up "start" codes, and control was restored.
"Most scientists did not believe that RNA-transfer-initiator could be involved in such an early stage of protein production, but the results we received remove all doubt," says Prof. Yosef Sperling. Prof. Ruth Sperling adds: "There is concern that segments containing 'stop' codes that enter the splicing process, and are mistakenly included in the instructions for protein production, may be involved in cancer and other diseases. Our findings show how such a mistake could happen."
