Wednesday , March 22 2023

The lack of a genetic repair system leads to a chromosome chaos


Scientists at the German Center for Cancer Research (Deutsches Krebsforschungszentrum, DKFZ) have now found the reason for frequent catastrophic events in cellular cancer cell genes that are known for only a few years: if an important DNA repair system fails, this promotes fragmentation and incorrect assembly of the genetic materials. Cancer cells with this defect repair can now be treated by a particular group of drugs.

Only a few years ago, researchers from the German Center for the Research of Carcinomas (DKFZ), among others, described the new form of damage in the genetic material of cancer cells: In an extremely aggressive type of brain tumor in childhood, unexpected chaos in the cell nucleus was discovered: the sections of individual chromosomes interrupted by innumerable points and wrongly folded so that all parts are missing, while others have been duplicated or embedded in the wrong orientation. This chromosome disorder was different from all previously known genetic defects in tumors.

Scientists use the term chromotrypsis to describe such a genetic disaster, which occurs in about twenty to thirty percent of all cancers. The trigger for this has so far been largely unknown. Aurelie Ernst and her team at the German Center for Cancer Research are now able to show that the failure of certain genetic repair systems is one of the causes of chromosomal chaos.

Many environmental impacts, such as UV rays, damage DNA. Cells have arsenal mechanisms to repair such defects. What happens if one of these systems fails? The Aurelie Ernst team tested this on genetically modified mice. In these animals, the tools that this cell used to repair DNA cells were genetically excluded – especially in cell precursor cells.

These mice were developed by malignant brain tumors (medulloblastomas and high-grade gliomas), which showed high-frequency chromotrypsis. The researchers noted that this is almost always followed by additional copies of the Mic oncogene, which is known to be a strong growth cell. "If the DNA repair is defective, and Mic nevertheless encourages the division of these damaged cells, the risk of chaos in the genome is particularly high," explains the DKFZ researcher.

Is this connection between defective genomic repair and chromosome chaos also applied to human cancers? Aureli Ernst and her team can confirm this for tumors of the brain, melanoma and breast cancer. The researchers also discovered the involvement of Mic, which promotes cancer in human tumors.

"The chromosome chaos caused by defect repair is at first glance frightening," explains Aurelie Ernst. "There are, however, ways to specifically fight against cancer cells that have such deficiencies: we can use drugs to further exclude another important DNA repair system, which leads to so many genetic damage that the cell can not survive. Hands that have all of their systems repair, do not interfere with these medicines. "

PARP inhibitors are already approved drugs that block the central DNA repair system. It is also possible to develop other substances that bind to other enzymes for DNA repair. "If the analysis of the patient's tumor gene reveals chromotryps evidence, treatment with PARP inhibitors can be a new therapeutic option in the future," explains DKFZ researcher Ernst. "Of course, this must be confirmed in preclinical and clinical tests.

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