Science: "Mysterious genes" mature the skeleton of cells

Geneticist Thijn Brummelkamp, when asked why he excels at tracking proteins and genes that others have not found, replied: "I am a professional needle finder in a haystack," and although some proteins and genes have been elusive for four decades, his team at the Dutch Cancer Institute has once again succeeded in tracking down one of these "mysterious genes," the gene that ensures the final form of the protein actin.
This is a major component
of our cytoskeleton.
The findings were published in the
journal Science.

Cell biologists are very interested in actin actin because we produce more than 100 kilograms of actin in our lifetime, which is the main component of the cytoskeleton and one of
the most abundant molecules in cells.
A lot of calcium can be found in every cell type, and it has many uses: it shapes cells and makes them firmer, it plays an important role in cell division, it pushes cells forward and provides strength
to our muscles.
People with actin deficiency often suffer from muscle disease
.
We already know a lot about the function of actin, but how is the final form of this important protein formed, and which gene is behind it?" We don't know," said Brummelkamp, whose mission is to find out the function of
our genes.

The genetics
of haploid human cells Over the course of his career, Brummelkamp has developed many unique methods for this purpose, which made him the first person
to inactivate genes on a large scale in human cells 20 years ago.

"You can't cross humans like a hybrid fruit fly and see what
happens.
" Since 2009, Brummelkamp and his team have been using haploid cells that contain only one copy of the gene instead of two (one from your father and one from your mother
).
While the combination of these two genes forms the basis of our entire existence, it also makes unnecessary noise when performing genetic experiments, because mutations usually occur in only one version of the gene (for example, the one from the father) and not in another
.

The multi-purpose human cytogenetics approach, along with other researchers, Brummelkamp uses this multi-purpose approach
to look for the genetic causes
of specific conditions.
He has discovered Ebola and a number of other viruses, as well as how some forms of chemotherapy have successfully entered cells
.
He also studied why cancer cells are resistant to certain types of treatments and found that there is a protein in cancer cells that suppresses the immune system
.
This time, he went looking for a gene that matured actin—and the result was the skeleton
of the cell.

Finding scissors
before a protein is fully "done" or, as the researchers describe it in the journal Science, before it matures — and before it can fully function in a cell, it usually has to be stripped of a particular amino acid
.
Then use a pair of molecular scissors to cut this amino acid off the protein
.
The same goes for
actin.
It is known which side of actin the associated amino acid is cut off
.
However, no one managed to find the enzyme
that acts as a scissor in this process.

Peter Haahr, a postdoc in Brummelkamp's team, conducted the following experiments: First, he caused random mutations (errors)
in random haploid cells.
He then selects cells containing immature actin and adds fluorescently labeled antibodies to the cells that fit just where
the amino acids are cut off.
As a third and final step, he studied which gene was mutated
after the process.

They called it ACTMAP
The moment was "a flash of inspiration": the researchers found molecular scissors that cut essential amino acids from actin
.
It turns out that these scissors are controlled by a previously unknown functional gene; No researchers have
worked with it.
This means that the researchers were able to name the gene themselves, which they identified as ACTMAP (ACTin MAturation Protease, ACTin Mature Protease, Biopass
).

To test whether the lack of ACTMAP would cause problems for the organism, they turned off the genes
in mice.
They observed that actin in the cytoskeleton of these mice was still not completed, as
expected.
They were surprised to find that the mice did survive, but the muscles were weak
.
The researchers conducted the study
together with scientists from the University of Amsterdam.

The discovery of more scissors
in the cytoskeleton ACTMAP is not the first mysterious gene
found by Brummelkamp to play a role in cytoskeleton function.
Using the same method, his team has been able to detect three pairs of unknown molecular scissors
.
In recent years, researchers have cut an amino acid
from tubulin, another major component of the cytoskeleton.
These scissors allow tubulin to properly perform its dynamic function
within the cell.
The discovery and description of the last pair of scissors (MATCAP) has also been published
.
Through early studies of the cytoskeleton, Brummelkamp successfully obtained actin
.

"Unfortunately, our new findings
on actin don't tell us how to treat certain muscle diseases," Thijn Brummelkamp said, "but we provide new basic knowledge about the cytoskeleton, which may be useful
to others later.
" In addition, Brummelkamp's task is to one day be able to map out all the functions of our 23,000 genes, and he can sketch out a new gene
from his vast list.
" After all, we don't know what half of our genes do, which means we can't intervene
when something goes wrong.