How yeasts manage to compensate for the genetic imbalance of extra chromosomes

Having extra chromosomes is usually a problem for an organism and can disrupt development or cause disease. But some cells benefit instead. For example, cancer cells or pathogenic yeast can use extra chromosomes to escape treatment and become drug-resistant.

A team of researchers from Charité-Universitätsmedizin Berlin has now deciphered how yeast manages to compensate for the genetic imbalance. Their findings, published in the journal Nature may lead to new approaches to the treatment of treatment-resistant tumors or fungal infections.

The typical healthy human cell has exactly two copies of the 23 chromosomes, where all of the person’s genetic information is stored. If an error occurs during cell division, resulting in three or more copies of a chromosome, this is a very good thing. Genes present on the double chromosome are “read” more often in general, so their products – proteins – are built at abnormal levels.

This can disrupt an organism’s development, as in the case of trisomies such as Down syndrome, or make an organism unstable in the first place. This makes aneuploidy, the medical term for an abnormal number of chromosomes, a frequent cause of miscarriage.

Surprisingly, however, there are also cells and organisms that have learned to cope with gene redundancy and even benefit from it. Some cancer cells, for example, can use extra chromosomes to better defend themselves against tumor drugs and continue to grow despite treatment.

Aneuploidy is also very common in yeast, a type of single-celled fungus: It is estimated that one fifth of all natural strains of the bread or wine yeast Saccharomyces cerevisiae have one set of abnormal chromosomes.

All proteins are exchanged faster

Researchers have been studying how these cells manage to deal with extra chromosomes for years. A research group headed by Prof. Markus Ralser, Director of the Biochemistry Institute at the Charité, has now traced a previously unknown compensation mechanism based on a yeast species.

“We were able to show that naturally occurring aneuploid yeast cells mitigate the damaging protein load by turning over all proteins more quickly,” explains Ralser.

For their study, the researchers compared “genetically healthy” yeast strains against strains in which aneuploidy had been induced in a laboratory and others that had been isolated from a wide variety of environmental areas around the world and had abnormal chromosome numbers from nature. Unlike the lab-grown species, the natural ones had to get used to the excess chromosomes.

For each of the approximately 800 strains studied, the researchers determined gene activity and the amount of all proteins. To do this, they used mass spectrometry, a method that can be used to measure hundreds of proteins from a single sample.

Analysis of these large amounts of data showed that most strains that had been aneuploid for a long time had compensated for the proteins encoded by the extra chromosome, meaning that these proteins were present at levels more similar to yeast healthy.

The team then studied how yeast achieved this. “Our data show that a system called the proteasome system is increased, which means that the cellular recycling machinery is more active,” explains Dr. Julia Münzner, the first author of the study, who works at the Institute of Biochemistry at Charité.

“So cells with extra chromosomes are going full blast, producing a lot, but they’re also faster at breaking down those products.”

This reduces the volume of additional proteins, although the turnover of other proteins is also faster. The researchers suspect that cells have another way of stabilizing non-redundant proteins so they don’t break down too much.

An approach to tackle drug resistance?

Researchers hope the new findings could be used as an approach to combat treatment-resistant tumors and fungal infections. Like cancer cells, pathogenic yeasts such as Candida albicans can become drug-resistant if they have extra chromosomes. Fungal infections that are no longer treatable can be fatal.

“For example, it would be conceivable to use drugs to slow down the breakdown of proteins in cells so that they turn around in the face of a high protein load,” says Ralser.

“This may be a way to prevent resistance to treatment.” For this approach to work, cancer cells and pathogenic yeasts must implement a principle similar to that found in Saccharomyces cerevisiae to tolerate aneuploidy. Finding this out is the research group’s next objective.