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Discovery of new mechanism for tumour suppression

8th June 2018


A group of researchers from Innsbruck has been the first to describe how damaged cells can be inhibited from multiplying further after incomplete division. In a project funded by the FWF, the team disproved the previous assumption that the mechanism is triggered by defective genetic information.

Errors in cell division can give rise to the development of cancer cells, which is why the investigation of these errors is of particular interest to scientists. Incomplete cell division is one such error: the cell prepares for division, the chromosomes are duplicated, but the actual division (cytokinesis) does not take place. The resulting cell is called “tetraploid” – “tetra” meaning four – because, unlike healthy cells, it carries four instead of two sets of chromosomes. While the cell is still perfectly viable, the problem arises at the next cell division, since not only the genetic information is duplicated, but also the number of centrosomes. The latter are important cell organelles whose function is to arrange the chromosomes correctly for division. This leads to asymmetric cell division and, subsequently, a wide variety of DNA defects, which may trigger the development of cancer.

In a basic-research project funded by the Austrian Science Fund FWF, a research group led by Andreas Villunger from the Medical University of Innsbruck has now been able to obtain clarity on an important mechanism relating to how the body protects itself from this scenario by inhibiting the further division of damaged cells or consigning them to controlled cell death.

Function of the p53 tumour-suppressor protein
“We have been working on cell death for a long time, particularly with the p53 tumour suppressor”, says Villunger. The p53 protein is of central importance for cancer research: “In more than 50% of all tumour patients, the protein is mutated or lost.” This impairs its tumour-suppressing function. It was known that p53 is also activated in tetraploid cells or the accumulation of centrosomes in order to inhibit cell division. “This has been known for a very long time”, explains the researcher, “but we did not know how the cell triggers this activation”.

Activation of p53 in case of incomplete cell division
Villunger’s group has now investigated a protein complex named PIDDosome. While it was assumed to be associated with p53 and cell death, more detailed knowledge was not available. Tetraploidy or centrosomes were not a priority focus of the project from the outset, but the investigations revealed surprising insights: “We have seen that a certain protein of the complex is activated when cells make mistakes during division and are unable to complete the final step, i.e. cytokinesis.” This is exactly the scenario that gives rise to tetraploid cells with twice the number of chromosomes and centrosomes. When the researcher group deactivated the PIDDosome complex, the cell’s own correction mechanisms for tetraploid cells no longer worked, and in particular the activation of p53 was absent. The team thus showed that there is a direct connection.

Closing a comprehension gap
“That was the initial observation,” says Villunger. “We were able to show that all proteins in this complex are involved in the process. We have also seen that the trigger signal is not the duplication of chromosomes, but the duplication of centrosomes.” Before every cell division, a second centrosome is formed in order to ensure the equal distribution of chromosomes to the two daughter cells. Tetraploid cells with incomplete division have two centrosomes which duplicate before the next division and thus lead to asymmetric cell division, including an uneven distribution of chromosomes.

An important gap in the understanding of how p53 is activated was thus closed. Researchers had suspected that the effect existed, but had concentrated on DNA. The fact that centrosomes have such a vital part in the process came as a great surprise to Villunger and his group. “Actually, we are interested in cell death following DNA damage. But then we saw that it was not DNA damage that activated p53, but the excess centrosomes. This does not necessarily lead to cell death, but it stops the cell cycle.” The cell no longer divides.

Basic-research project with unforeseeable outcome
The unexpected result of this project, which was approved by the FWF only upon its third submission, has now opened the door to new research enabling Villunger’s team to land an ERC grant from the European Research Council which fosters excellence in research. The grant is endowed with several million Euros. Villunger emphasises how important it is to engage in basic-research projects which can respond flexibly to interesting new findings. “With the original project we simply intended to obtain an insight into whether and how this little-understood protein complex is involved in regulating cell death. But when we saw the interesting results on the centrosomes we changed tack and focused on that.”

Villunger is particularly interested in the fact that the duplication of chromosomes is produced deliberately in some organs and plays an important role in differentiation. “There are many tetraploid cells with extra centrosomes in the liver,” says Villunger. “We have seen that the PIDDosome is required there as well to activate p53.” Villunger concedes that they were initially betting on the wrong horse, but he also emphasises that research does not always progress in a straight line: “The hypothesis of the original project proposal was not correct. But in the end we were able to shed light on a mechanism whose existence had been suspected for many years, which had not been understood at molecular level.” His research has provided a deeper understanding of the tumour suppressor p53, created potential routes for future cancer therapies and opened up a number of new research fields.





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