TOPICS: UniversityVU CellsGeneticsProtein
The gene that the researchers discovered ensures that actin, an important part of our cell skeleton, is created in its final state.
The cell skeleton becomes developed thanks to the gene.
Thijn Brummelkamp, a geneticist, said, “I’m a professional pin-in-a-haystack finder. I identify proteins and genes that others have missed, even though some have been elusive for as long as forty years.” One of these “mystery genes,” the gene that ensures the final form of the protein actin, a crucial element of our cell skeleton, is created, has once more been discovered by his research team at the Netherlands Cancer Institute. The journal Science just published these discoveries.
Cell scientists are particularly interested in actin since it is one of the most prevalent molecules in a cell and a crucial constituent of the cell skeleton. We make more than 100 kilos of actin over our lifetime. It is abundantly found in all cell types and serves a number of purposes, such as giving cells shape and firmness, being a crucial component of cell division, causing cells to advance, and giving our muscles strength. Muscle illness is frequently present in people who have faulty actin proteins. The purpose of actin is well understood, but how is the finished product made and which gene is in charge of this essential protein?
actin microscopy picture. (Cell core is blue, actin is yellow.) Credit: Netherlands Cancer Institute/Peter Haarh
Human haploid cell genetics
Over the course of his work, Brummelkamp has created a number of novel techniques for this purpose, enabling him to pioneer the large-scale inactivation of genes for his genetics research in human cells twenty years ago. “You can’t crossbreed people and observe what occurs, way you can with fruit flies.” Brummelkamp and his group have been utilising haploid cells since 2009, which are cells with only one copy of each gene rather than two (one from your father and one from your mother). Our entire existence is based on this pair of genes, but it also introduces undesirable noise into genetic experiments because mutations often only affect one copy of a gene (such as the one from your father) and not the other.
a versatile technique for studying genetics in human cells
This versatile approach is used by Brummelkamp and colleagues to identify the genetic origins of specific illnesses. He has already demonstrated how several viruses, including the Ebola virus and others, as well as specific types of treatment, may enter a cell. He also looked into the reasons why some forms of therapy are ineffective against cancer cells, and he found a protein in cancer cells that inhibits the immune system. This time, he searched for a gene that grows actin, which affects the cell’s skeleton.
looking for scissors
A protein often needs to be stripped of a certain amino acid before it is fully “finished” – or mature, as the researchers put it in Science – and can fulfil its function in the cell. Then, using a pair of molecular scissors, this amino acid is separated from a protein. Actin also behaves in this way. On which side of the actin the pertinent amino acid is cut off, it was known. Nobody has, however, been able to identify the enzyme that functions as the process’s scissors.
In the experiment described below, Peter Haahr, a postdoc in Brummelkamp’s lab, first randomly mutated (erred) haploid cells. He then chose the cells that contained the immature actin by including an antibody that was fluorescently tagged and matched the precise location where the amino acid is removed in his cells. He then looked into which gene changed as a result of this process as the third and last step.
It was known as “ACTMAP.”
Then came the “aha!” moment: Haahr had discovered the molecular shears responsible for severing actin’s crucial amino acid. That gene, whose function was previously unknown and with which no researcher had ever studied, turned out to be in charge of those scissors. This indicates that the researchers had the ability to give the gene its own name; they chose ACTMAP (ACTin MAturation Protease).
They turned off the ACTMAP gene in mice to see if the absence of the protein causes problems in living beings. They saw that, as they had anticipated, the actin in the cell skeleton of these mice remained incomplete. They were shocked to learn that the mice did survive, although they had weak muscles. This study was carried out in collaboration with VU Amsterdam experts.
More scissors were discovered in the cell’s skeleton.
Brummelkamp’s discovery of a mystery gene involved in the operation of our cell skeleton is not limited to ACTMAP. His team has discovered three unidentified molecular scissors that cut an amino acid from tubulin, the other major part of the cell skeleton, in recent years using the same technique. Tubulin can adequately carry out its dynamic tasks inside the cell thanks to these scissors. This year, the final scissors (MATCAP) were found and described in Science. Brummelkamp arrived at actin through his earlier research on the cellular skeleton.
The goal is to map all 23,000 genes.
Thijn Brummelkamp laments that “unfortunately, our new understanding concerning actin does not inform us how to repair some muscular disorders.” However, we have added new fundamental understanding of the cell skeleton that may eventually be helpful to others. Additionally, Brummelkamp can cross another gene off his enormous list as he works toward his goal of one day being able to map out the functions of all 23,000 of our genes. Because we are unaware of the functions of half of our genes, we are powerless to correct problems when they arise.
Reference: “Actin maturation needs the ACTMAP/C19orf54 protease,” published in Science on September 29, 2022, by Peter Haahr, Ricardo A. Galli, Lisa G. van den Hengel, Onno B. Bleijerveld, Justina Kazokait-Adomaitien, Ji-Ying Song, Lona J. Kroese, Paul Krimpenfort, Marijke P. Baltissen, Mic