The failure of the gene repair system leads to chromosomal chaos

Scientists at the German Center for Cancer Research (Deutsches Krebsforschungszentrum, DKFZ) have now found the cause of frequent catastrophic events in cancerous cancer cells that have been known for only a few years: if an important DNA repair system failed, this stimulates fragmentation and deficiencies assembly of genetic material. Now, cancer cells with such a defect can repair treatment with a specific group of medicines.

Only a few years ago, scientists from the German Center for Cancer Research (DKFZ) described, among others, a new pattern of the harmfulness of cancerous cell genetic material: in the particularly aggressive type of brain tumors in childhood, incredible chaos was detected in the cell nucleus: parts of individual chromosomes were broken down into countless points and incorrectly assembled, so that all parts were missing, others were duplicated or included in the wrong orientation. This chromosome disaster was different from all previously known genetic defects in tumors.

Scientists use the term chromotrypsis to describe such a genetic disaster that occurs in about 20 to 30 percent of all types of cancer. The trigger has so far been largely unknown. Aurelie Ernst and her team at the German Center for Cancer Research can now show that the failure of certain gene systems has been corrected by one of the causes of chromosome chaos.

Many environmental influences, such as UV rays, damage DNA. Cells have arsenal mechanisms to repair these defects. What happens if one of these systems fails? Aurelie Ernst tested this on genetically modified mice. In these animals, the tools used by the cell to repair double strands of DNA were genetically turned off – especially in nerve cell precursors.

These mice developed malignant tumors of the brain (medulloblastoma and high-performance glioma), which showed chromotrypsis at high frequencies. Researchers have noted that this is almost always accompanied by additional copies of Myc oncogene, which is known to be a powerful cell growth driver. "If DN repair is defective and Myc encourages the division of these damaged cells, the risk of chaos in the genome is particularly high," explains the DKFZ researcher.

Is the connection between defective genomic correction and chromosomal chaos also true for cancer? Aurelie Ernst and her team can confirm this for tumors of the brain, melanoma, and breast cancer. Researchers also found the inclusion of Myc, which promotes cancer, in human tumors.

"Chromosome chaos due to repair errors is at first glaring frightening," explains Aurelie Ernst. "There are, however, ways to specifically combat cancer cells that have such deficiencies: with medicines, we can further turn off another important DNA repair system, which causes so much genetic damage that the cell can not survive. Having all of its repair systems, not disturbs these medicines. "

PARP inhibitors are already approved medicines that block the central DNA repair system. Other substances may also be developed that are attributable to other DNA repair enzymes. "If the analysis of the patient's tumor genome reveals evidence of chromotrypsis, treatment with PARP inhibitors in the future could be a new therapeutic option," explains DKFZ Ernst. "Of course, this should be confirmed in pre-clinical and clinical tests.

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