Researchers of the University of Geneva (Switzerland) have revealed a new mutation mechanism that is essential for cancer development. In his work, published in the magazine Nature Communications, have linked DNA replication failures in cancer cells with their genetic instability.
When a cell divides into two, it must replicate its DNA according to a very specific scenario. However, in the presence of some disturbing elements, cancer cells are unable to perform this operation optimally, so replication is carried out more slowly and less efficiently. This phenomenon is called replication stress.
Although it is known that it is related to the increase in genetic mutations, another typical phenomenon of cancer cells, the exact mechanism discovered in this new work remained unknown until now.
During a normal life cycle, the cell grows and, when all the ‘building blocks’ necessary for DNA replication are ready, it replicates the chromosomes, which contain their genetic information. Once DNA replication is complete, the cell enters mitosis.
Next, an achromatic spindle is created, in which the two strands of replicated DNA are separated so that the two daughter cells inherit an identical number of chromosomes. “To ensure the correct distribution of chromosomes, the achromatic spindle has two poles. This bipolarization is essential for the genomic stability of both daughter cells, ”explains one of the researchers, Patrick Meraldi.
In most cases, the stress of replication is due to certain molecules that, when produced in excess, become harmful. For example, the cyclin E protein, involved in DNA regulation, promotes the development of cancers when it is overexpressed. In fact, under their influence, cancer cells tend to replicate too soon. They still don't have all the necessary components for DNA synthesis, and this is where the errors appear.
To decipher this phenomenon, the researchers artificially induced the stress of replication in healthy human cells with a product that slows DNA replication and, therefore, prevents the process from continuing normally. “We have observed that this stress causes a malformation of the achromatic spindle that, instead of having two poles, has three or four,” details another of the researchers, Therese Wilhelm.
The scientist adds that the cell is generally able to eliminate these supernumerary poles, but not fast enough to avoid erroneous connections between the chromosomes and the achromatic spindle. “In the end, these erroneous connections promote a poor distribution of chromosomes, leading to the loss or gain of one or more chromosomes. This genetic instability allows the rapid anarchic evolution of cancer cells, ”he reflects.
In their work, these scientists successfully corrected the effects of replication stress on diseased cells by providing them with the missing components for replication. “Not only have we established the link between replication stress and chromosomal errors, but we have been able to correct it, demonstrating that this phenomenon, present in all cancers and even in precancerous cells, is controllable,” says one of the authors, Anna-Maria Olziersky.
Through a series of experiments aimed at this mechanism, the researchers demonstrated the increased sensitivity of cells to abnormal achromatic spindle to paclitaxel, a chemotherapeutic drug that acts in the achromatic spindle and is used for the treatment of breast cancer.
“This shows that, in principle, it is possible to target these cells specifically without affecting healthy cells. The idea is not to correct the error, but rather to block the cell at this stage to prevent it from removing the additional poles, which automatically leads to its rapid death without causing damage to the still healthy neighboring cells, ”concludes Patrick Meraldi.