Monday , January 25 2021

The failure of the genetic repair system leads to chromosome chaos

Researchers from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered the cause of the most catastrophic events in the genetic material of cancer cells that have been known for several years: if an important DNA repair system failed, this encourages fragmentation and improper installation of genetic material . Cancer cells with such repair defect can now be treated with a certain set of drugs.

A few years ago, scientists from the German Cancer Research Center (DKFZ) described, among other things, a new pattern of cancer cell genetic damage: in a particularly aggressive type of childhood tumor, they discovered unusual chaos in the Cell Core: Single chromosome sections were broken into countless points and they were re-assembled so that all parts were missing, while others were duplicated or embedded in the wrong orientation. This chromosomal disaster differs from all previously known genetic defects in tumors.

Scientists use the term chromotrips to describe such a genetic catastrophe, which accounts for twenty to thirty percent of all types of cancer. The trigger for this has been largely unknown to date. Aurelie Ernst and her team at the German Cancer Research Center have now been able to show that the failure of certain genetic repair systems is one of the causes of chromosome chaos.

Many environmental impacts, such as UV rays, damage DNA. Cells have arsenal mechanisms to repair such disadvantages. What happens if one of these repair systems fails? Team Aurelie Ernst tested it on genetically modified mice. In these animals, tools that used a repair station for two double-stranded DNA carriers were genetically excluded – more specifically in neural precursor cells.

These mice developed malignant brain tumors (medulloblastomas and high grade gliomas), which showed high frequency chromotrips. The researchers noted that it was almost always followed by additional copies of the Myc oncogene, which is known as a powerful cell growth trigger. "If DNA repair is defective, and Myc encourages the division of these damaged cells, the risk of chaos in the genome is particularly high," explains DKFZ researcher.

Is this connection between faulty chromosome genome and chromosome repair also applicable to human cancers? Aurelie Ernst and her team can confirm this for brain tumors, melanomas, and breast cancer. Researchers also discovered the involvement of cancers that stimulate cancer in human tumors.

"Chaos chromosome caused by repair damage is quite scary," explains Aurelie Ernst. "However, there are ways to specifically fight against cancer cells that carry such deficiencies: we can use drugs to exclude another important DNA repair system, which results in so many genetic damage that the cell can not survive. Do not neglect these remedies. "

PARP inhibitors have already approved drugs that block the central DNA repair system. Other substances that bind to other repair enzymes of DNA may also be developed. "If the patient's genome scan of the tumor detects chromotypic evidence, treatment with PARP inhibitors may be a new therapeutic option in the future," explains researcher Ernst DKFZ. "Of course, this has to be confirmed in preclinical and clinical trials.

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