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The genes scientists discovered ensured the production
of actin, the main component of our cytoskeleton, in its final form.
Geneticist Thijn Brummelkamp replied when asked why he succeeded in finding proteins and genes that others missed
: "I'm a professional needle-in-a-haystack explorer.
" His team at the Netherlands Cancer Institute has once again identified one of these "mysterious genes" that guarantee the production
of the final form of actin, a key component of our cytoskeleton.
The findings were recently published in
the journal Science.
Actin is one of the most common molecules in cells and a key component of the cytoskeleton, which is why
it is of particular interest to cell biologists.
We produce more than 100 kg of actin
in our lifetime.
It is abundant in all types of cells and has a variety of functions, including giving cells structure and making them firmer, playing a key role in cell division, pushing cells forward, and giving our muscles strength
.
People with deficient actin usually suffer from muscle disease
.
We already know a lot about actin's function, but how is the final version of this important protein produced, and which gene is responsible?
"We don't know," says Brummelkamp, whose mission is to figure out the function of
our genes.
Over the course of his career, Brummelkamp has developed a number of unique methods for this, which led him to become the first person
to massively inactivate genes in human cells 20 years ago.
"You can't cross humans like you do a fruit fly and see what happens
.
" Since 2009, Brummelkamp and his team have been using haploid cells, which contain only one copy of a gene, rather than 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 conducting genetic experiments, because mutations usually occur in only one version of a gene (for example, the one from the father) and not in another
.
Together with other researchers, Brummelkamp uses this versatile approach to finding genetic causes
for specific conditions.
He has shown how Ebola and some other viruses, as well as some forms of chemotherapy,
successfully enter cells.
He also looked at why cancer cells are resistant to certain types of treatments and found that there is a protein present in cancer cells that suppresses the immune system
.
This time, he looked for a gene that matured actin — and the result was the skeleton
of the cell.
Before a protein can be completely "finished" — or, as the researchers describe it in Science, before it matures — and can fully perform its function in the cell, it must usually be stripped of a specific amino acid
.
This amino acid is then cut out
of the protein with a pair of molecular scissors.
The same goes for
actin.
It is known which side of actin the relevant amino acids are cut
.
However, no one has managed to find the enzyme
that acts as scissors in the 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 right where
the amino acids are cut.
As a third and final step, he studied which gene was mutated
after this process.
Then came the "flash of light" moment: Haahr 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 meant that the researchers were able to name the gene themselves, which they identified as ACTMAP (ACTin maturation protease).
To test whether a lack of ACTMAP caused problems in the organism, they turned off the genes of the
rats.
They observed that actin in the cytoskeleton of these mice remained unfinished, as expected
.
They were surprised to find that the mice did survive, but their muscles were weak
.
The researchers conducted the study
together with scientists from the University of Amsterdam.
ACTMAP is not the first mysterious gene
discovered by Brummelkamp that plays a role in cytoskeletal function.
Using the same method, his team has been able to detect three unknown molecular scissors in recent years that cut an amino acid
from tubulin, another major component of the cytoskeleton.
These scissors allow tubulin to properly perform its dynamic functions
within the cell.
The last pair of scissors (MATCAP) was discovered and published in this year's
journal Science.
Through early studies of the cytoskeleton, Brummelkamp succeeded in obtaining actin
.
"Unfortunately, our new findings about actin don't tell us how to treat certain muscle diseases," says
Thijn Brummelkamp.
"But we provided new basic knowledge about the cytoskeleton that might be useful
to others later.
" In addition, Brummelkamp is tasked with one day being able to map all the functions of our 23,000 genes, and he can tick off one more 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.
Reference: Actin maturation requires the ACTMAP/C19orf54 protease
