Geneticist Thijn Brummelkamp replied when asked why he could successfully find the protein and genes that others missed, "I am a professional pin-in-a-haystack seeker, although some people have been unable to find it for up to forty years."
It is reported that his team at the Dutch Cancer Institute once again discovered one of these "mysterious genes" - a gene that ensures the final form of protein actin (a key component of our cytoskeleton ). These findings were recently published in Science.
Actin is one of the most common molecules in cells and a key component of the cytoskeleton, which is why cell biologists are particularly interested in it. Throughout our lives, we produce over 100 kilograms of actin. It is present in all types of cells and has multiple functions, including conferring cell structure and making it stronger, playing a key role in cell division , pushing cells forward and giving us muscle strength. People with actin defects tend to have muscle diseases. There is a lot of knowledge about the function of actin, but how is the final version of this important protein produced and which gene is responsible for it? "We don't know," said Brummelkamp. His task is to find out what our genes do.
Brummelkamp has developed many unique methods for this in his career, which allowed him to become the first genetics study of human cells on a large scale to inactivate genes twenty years ago. Since 2009, Brummelkamp and his team have been using haploid cells—a cell with only one copy of each gene, not two (one from the father and one from the mother). While this combination of two genes forms the basis of our entire existence, it also produces unnecessary noise when performing genetic experiments, as mutations usually occur only in one version of the gene and not the other.
Together with other researchers, Brummelkamp uses this multipurpose approach to find genetic causes for specific conditions. He has shown how Ebola virus and some other viruses and some forms of chemotherapy manage to get into the cells. He also studied why cancer cells are resistant to certain types of treatments, and also discovered a protein found in cancer cells that acts as a brake on the immune system. This time, he went to find a gene that matures actin -- and thus the skeleton of the cell.
before a protein is completely "completed" and able to fully function in the cell, it usually has to be stripped off a specific amino acid . Then use a pair of molecular scissors to cut this amino acid off the protein. This is also happening with actin. It is known that the relevant amino acids are cut off on which side of actin. Yet no one has managed to find the enzyme that acts as scissors in the process. Peter Haahr, a postdoctoral fellow in the Brummelkamp group, conducted the following experiment: First, he caused a random mutation (error) in random haploid cells. He then selects cells containing immature actin by adding a fluorescently labeled antibody to the cells, which is just right at the location where the amino acid is cut off. As the third and final step, he investigated which gene mutated after this process.
Then the "I found it" moment: Haahr has tracked down the molecular scissors that cut essential amino acid from actin. The scissors turned out to be controlled by a gene with previously unknown functions; none of the researchers worked with it. This means that the researchers were able to name the gene themselves, and they identified ACTMAP (ACTin MAturation Protease).
To test whether the lack of ACTMAP would cause problems with the organism, they turned off the mouse genes. They observed that actin in the cytoskeleton of these mice was still not completed. They were surprised to find that the mice did maintain their vitality, but suffered from muscle weakness. The researchers conducted the study with scientists from the University of Amsterdam .
ACTMAP is not the first mysterious gene found by Brummelkamp to play a role in our cytoskeleton function. By using the same method, his team has been able to detect three unknown molecular scissors in recent years that cut an amino acid from another major component of the cytoskeleton, tubulin. These scissors allow the tubulin to perform its dynamic function normally within the cell. The last pair of scissors (MATCAP) was discovered and described in this year's Science. Through early research on the cytoskeleton, Brummelkamp successfully reached actin.
"Unfortunately, our new discovery about actin doesn't tell us how to treat certain muscle diseases," said Thijn Brummelkamp. "But we have provided new basics about the cytoskeleton that may be useful to others in the future." Additionally, Brummelkamp's mission is to one day map out all of our 23,000 genes, and he can ticke another new gene from his huge list. After all, we don’t know what half of our genes do, which means we can’t intervene when something goes wrong.
