Ready, set, go: how the genetic code points out the start site of protein production – PhD defense Bram Verhagen

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On May 8th, Bram Verhagen defended his dissertation ‘Where to start? How gene sequences shape translation initiation’. He studied how ribosomes in human cells can recognize the start of the coding sequence in mRNAs. The coding sequence in mRNAs is a piece of genetic code that contains the blueprint for a protein. In his research, he discovered new sequences that assist the ribosome in identifying the beginning of coding sequences. This new information allows for a better understanding of gene expression regulation and could provide insight into the effects of gene mutations on protein production. Additionally, the results could improve the production of proteins for medication and/or industrial purposes in the future. He conducted his research in the Tanenbaum group.

All genetic information of an organism is stored in DNA. You can compare DNA to a cookbook, which contains different recipes for different proteins. Proteins perform all kinds of important tasks in cells; some, for example, help break down sugar, and others have an important transport function in the cell. Prior to the production of a protein, a part of the DNA is copied into mRNA. This copy is used by ribosomes, which you could consider the chefs in this analogy. The ribosomes convert the recipes in mRNAs into dishes, the proteins. The genetic information in DNA and mRNA consists of nucleotides, comparable to letters that make up the “recipes”. The order of these nucleotides, the sequence, determines which protein is made. Ribosomes use only a specific part of the mRNA, the coding sequence, to produce a protein. However, it is not always clear where this sequence starts. If the ribosome does not recognize the correct start site, it can cause problems. For example, shortened proteins with altered functions can be produced when the ribosome misses the correct starting point.

Important tool?

Previous research has shown that there is a specific genetic code in mRNAs that helps ribosomes recognize the start of the coding sequence. This “Kozak sequence” thus increases the production of the correct proteins by ribosomes. This sounds like a very important tool, yet there are many mRNAs that do not contain a Kozak sequence. “What we noticed was that only a small set of all mRNA contains the Kozak sequence,” Verhagen explains, “this led to some interesting questions.”: Why don’t all genes use the Kozak sequence? Is this sequence really necessary to properly recognize the beginning of the coding sequence? Are there other sequences in the mRNA that help ribosomes find the beginning of the coding sequence? These are the questions Verhagen addressed during his PhD.

Scanner reveals more tools

To investigate these questions, Verhagen has developed “RiboScan”. RiboScan is a new tool that can be used to measure how well ribosomes can recognize the start of the coding sequence. Verhagen’s PhD research shows that the Kozak sequence is not the only tool ribosomes use to recognize the correct start of the coding sequence. Other pieces of genetic code within the mRNA can also help find the starting point of the coding sequence, even when a Kozak sequence is present in the mRNA.

Verhagen discovered in his research that even within the coding sequence, there are pieces of genetic code that can affect how well ribosomes recognize the start. “So, the coding sequence is not just a blueprint for making proteins, but can also have additional functions such as regulating the amount of protein that is produced,” Verhagen elaborates.

Medication, mutations and more

Since proteins can only be made correctly when ribosomes recognize the correct starts of coding sequences, the possible applications of this research are also very broad. One possible application of the results of this research is to make the production of proteins for medical and/or industrial purposes more efficient. The pieces of genetic code newly discovered in this research could be used to improve mRNA sequences such that ribosomes can convert the genetic information into proteins more efficiently. This could offer advantages in the production of drugs, which can consist of proteins. Furthermore, the knowledge gained from this research can be used to determine the effects of mutations around the start of the coding sequence on protein production, which may give us a better picture of certain diseases.

Collaborations and the unknown

One of the biggest challenges, while also a big motivation, for Verhagen during his PhD was investigating something that had never been studied before. He says that as a result, during his PhD there was sometimes no one to explain to him why an experiment did not work. But that it was also satisfying when it did eventually yield new insights. Additionally, Verhagen was able to get support from collaborations with others: “They often led to lasting friendships that I value greatly” Verhagen says. He talks about his collaboration with a research group in Göttingen working on a model that represents the interaction between the ribosome and mRNA. Furthermore, Verhagen looks back on his collaboration with Jeroen de Ridder’s research group at UMC Utrecht that is using AI to gain insight into large data sets he collected during his PhD. Finally, Verhagen talks about his colleagues at the Hubrecht Institute who were always ready to provide a listening ear and input. Finally, Verhagen wants to assure aspiring and beginning PhD students: “Don’t give up and stay curious, a PhD is a marathon, just keep going!”

Bram will celebrate his PhD with a dinner with his family, paranymphs and Marvin Tanenbaum. Afterwards, he will throw a party for friends, family and (former) colleagues at a café. Bram is looking forward to his vacation to Canada and will then continue his research career as a postdoc, first for a while with Marvin Tanenbaum and then in Arnaud Krebs’ group at EMBL Heidelberg.