Weizmann Institute of Science scientists have put thousands of proteins in baker's yeast on surprise "strike" and revealed unknown functions related to the most basic functions of life.
Employers tend to think that every worker has a replacement, and at least for most proteins – the workers of our body’s cellular factories – this is true. If we permanently eliminate a protein, that is, if we delete its gene from the genome through genetic engineering, the cell will usually activate an orderly process to replace it with other proteins. This compensatory mechanism is essential for the existence of life, but it makes it very difficult for researchers who want to learn the function of each and every protein. But what if we unexpectedly take out a protein for a “flash strike”? The cell will not have time to find replacements, and thus the role of the unruly striker may be revealed. In a new study published inThe scientific journal Journal of Cell BiologyScientists at the Weizmann Institute of Science "installed" thousands of "shutdown machines" in yeast colonies and used them to reveal essential functions of many proteins that were previously mysterious.
Baker's yeast, familiar to us from the bread and beer industries, shares about two-thirds of its genes with us, which is why it has become one of the most studied creatures in nature. The yeast's genetic material contains about 6,000 genes that code for proteins, and despite decades of research, the functions of about 1,200 of them remain a mystery. In the new study, Prof. Maya Schuldiner The Institute's Department of Molecular Genetics attempted to trace their functions. They did this using a system that allows a protein to be quickly removed from the cell, that is, to be put out of action "at the push of a button." The system consists of three parts - a tag with which the protein that you want to study is marked, a destroyer protein whose job is to break down the marked protein and inactivate it - and an intermediary substance in the presence of which the inactivation occurs.
The research team, led by doctoral student Rosario Valenti and Dr. Yotam David from Prof. Schuldiner's lab, did not install the inactivation system in a single gene, but rather used genetic engineering methods to create an entire genetic library – a collection of 5,170 yeast strains, each of which has a different protein marked for inactivation. "With the help of the Institute's computing infrastructure branch, we built a digital library that anyone can visit and query the genetic strains for research purposes," says Prof. Schuldiner. "In the library, you can not only find the yeast strains themselves, but also learn what the effect of the 'inactivation' was."
Understanding the role of mysterious genes and proteins in yeast is not just a matter for researchers of single-celled organisms; through these discoveries, we can learn about the role of many parallel genes in human cells. "Many rare genetic diseases have a known cause, but because we don't know what the function of the defective gene is, there is no treatment," explains Prof. Schuldiner. "We share with yeast many hundreds of mysterious proteins whose function could be a key to understanding unsolved diseases." Prof. Schuldiner is particularly interested in genes essential for mitochondria - compartments in the cell that constitute "power plants" that produce chemical energy for the entire cell. It is known that there is a connection between the shape of mitochondria and their distribution in the cell and their function - for example, when they are connected to each other, they tend to convert energy more efficiently.
The cell is constantly adapting the structure of the mitochondria to its needs, and failure to do so is the cause of many diseases. Surprisingly, not all the details are known about the mechanism that changes the arrangement of the power plants in the cell, and even less is known about the factors that regulate it. Using the new library, the scientists discovered 220 genes whose inactivation damaged the structure of the mitochondria in the cell and identified which of them are important for maintaining a normal rate of chemical energy production.
Similarly, the scientists used the library to investigate which proteins are important for the cell's life cycle and identified new proteins that schedule the division cycle. In total, the research team identified the roles of hundreds of genes that were not previously known to be necessary for cell survival. These genes were revealed to be essential in certain growth environments, but in addition, several genes were also revealed that are necessary for the cell in any condition and were not known to be so until now.
The new library is already making waves: "Laboratories around the world have begun to borrow individual strains from us in order to deepen the study of proteins whose functions are unknown," shares Prof. Schuldiner. "Laboratories are also invited to borrow entire sections of the library and use them to investigate which components are important for a particular cellular process, as we demonstrated in the study. I hope that in the coming years the library will help to remove the veil of mystery from some of the processes that occur in human cells in health and disease."
Also participating in the study were Donia Edelby, Dr. Benjamin Dubroy, Yinit Asraf and Dr. Ehud Shesh, from the Institute's Department of Molecular Genetics; Angela Bushnikowska and Prof. Peter Rehling from the University Medical Center in Göttingen, Germany; and Dr. Tomer Meir Selma from the Institute's Department of Life Sciences Research Infrastructures.
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