Image: Human chromosomes © CDC | Suzanne Trusler, MPH, DrPH
Berlin, 22 May, 2024
As a rule, too many chromosomes are a problem. They disrupt the development of an organism or lead to diseases. However, some cells benefit from this: for example, cancer cells or pathogenic yeast fungi can ‘protect’ themselves from drugs by altering their chromosome set. A research team from Charité – Universitätsmedizin Berlin has now deciphered how yeast fungi manage to compensate for an excess of chromosomes. The results, published in the journal Nature*, could provide new starting points for the treatment of therapy-resistant tumours or fungal infections.
A healthy human cell has exactly two copies of 23 chromosomes, on which all genetic information is stored. If a chromosome is present in three or more copies due to an error during cell division, it is too much of a good thing: Because the genes located on the multiplied chromosome are read more frequently overall, their products – the proteins – accumulate in large numbers. As a result, the organism is impaired in its development, for example in the case of trisomies such as Down’s syndrome, or is not viable in the first place. Aneuploidies – the technical term for the incorrect number of chromosomes – are therefore a common cause of miscarriages.
Surprisingly, however, there are also cells and organisms that have learnt to deal with the excess of genes and sometimes even derive an advantage from this. For example, some cancer cells with additional chromosomes are better able to defend themselves against tumour drugs and grow despite treatment. Aneuploidy is also very common in yeasts, i.e. unicellular fungi: an estimated one in five naturally occurring strains of the species Saccharomyces cerevisiae, known as baker’s or wine yeast, has an altered set of chromosomes.
All proteins are exchanged more quickly
How these cells manage to cope with the surplus chromosomes has been the subject of research for years. Using the example of a yeast species, a research group led by Prof Markus Ralser, Director of the Institute of Biochemistry at Charité, has now succeeded in elucidating a previously unknown compensation mechanism. ‘We were able to prove that naturally occurring aneuploid yeast cells buffer the damaging protein load by exchanging the entirety of all proteins more quickly,’ says Markus Ralser.
For the study, the researchers compared ‘genetically healthy’ yeast strains with those in which aneuploidy had been induced in the laboratory and others that had been isolated from various environmental niches worldwide and were naturally aneuploid. In contrast to the laboratory strains, these strains had been able to adapt to the excess chromosomes over a longer period of time. For each of the 800 or so strains analysed, they determined the activity of the genes and the quantity of all proteins. To do this, they used mass spectrometry, a method with which hundreds of proteins from a single sample can be measured. Analysing the huge amounts of data revealed that most of the strains that had been aneuploid for a long time had compensated for the proteins encoded by the surplus chromosome, i.e. their quantity was more similar to that of healthy yeasts.
The team then investigated how the yeasts achieved this. ‘Our data show that the so-called proteasome system is ramped up, meaning that the cellular recycling machinery is more active,’ explains Dr Julia Münzner, a scientist at Charité’s Institute of Biochemistry and lead author of the study. ‘Cells with excess chromosomes therefore run at full speed, they produce a lot, but also break down the products again at an above-average rate.’ This reduces the amount of excess proteins, but other proteins are also converted more quickly. The scientists assume that the cells stabilise the non-excess proteins by other means so that they are not decimated too much.
An approach against drug resistance?
The researchers hope that the new findings can be used for the treatment of therapy-resistant tumours as well as fungal infections. This is because, like cancer cells, pathogenic yeast fungi such as Candida albicans can also become resistant to drugs with the help of additional chromosomes. If they can no longer be treated, fungal infections can be fatal.
‘It would be conceivable, for example, to decelerate protein degradation in the cells with medication so that they have to deal with an increased protein load again,’ says Markus Ralser. ‘It may be possible to prevent resistance to therapy in this way.’ The prerequisite is that cancer cells and pathogenic yeasts use a similar principle to Saccharomyces cerevisiae to tolerate aneuploidy. Finding this out is the next goal of the research group.
*Muenzner J et al. Natural proteome diversity links aneuploidy tolerance to protein turnover. Nature 2024 May 22. doi: 10.1038/s41586-024-07442-9
About the study
The study was led by Prof Markus Ralser and Prof Judith Berman. Markus Ralser is Einstein Professor of Biochemistry and heads a research group at the Nuffield Department of Medicine at the University of Oxford in addition to the Institute of Biochemistry at Charité. Judith Berman is head of a research group at the Shmunis School of Biomedical and Cancer Research at Tel Aviv University. The work was carried out as part of a Synergy Grant from the European Research Council (ERC), which the two researchers obtained together.
Image: Staining of the DNA of a healthy human cell with a total of 26 chromosomes. Excess chromosomes usually cause a harmful genetic imbalance © CDC | Suzanne Trusler, MPH, DrPH