Failed DNA repair triggers chromosomal chaos

Researchers at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have established the trigger for catastrophic events that occur within the chromosomes of cancer cells and lead to cancer cell death.

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They found that failure of DNA repair systems promotes fragmentation and disrupted assembly of chromosomes. However, the researchers say that these DNA repairs can be treated with certain drugs.

Only a few years ago, scientists at the same research center reported that a particularly aggressive form of childhood brain tumor, unprecedented chaos occurred in the cell nuclei.

Sections of chromosomes have been broken at multiple points and incorrectly reassembled, while other sections have been incorrectly copied or incorporated.

These events, which scientists referred to as "chromothripsis," had not been seen before.

Chromothripsis occurs in around 20 to 30% of all cancers, but until now, it has been largely unknown what triggers this genetic disaster.

As reported in the newspaper Nature Communications, Aurélie Ernst and team identified the failure of certain genetic repair systems as one of the causes.

The team studied a mouse model where the tools used by neural precursor cells to repair broken DNA had been genetically switched off. As a result, the animals developed a high frequency of chromothripsis.

In addition, the chromothripsis almost always occurs in conjunction with cancer-promoting myc oncogene.

If the DNA repair is defective and Myc nevertheless stimulates the division of these damaged cells, the risk of chaos in the genome is particularly high.

Dr. Aurélie Ernst, Lead Author

The team confirmed that chromosomal events are also occurring in the melanoma, brain tumors and breast cancer in humans and the Myc oncogene is again involved.

Ernst says that the chromosome chaos caused by failed DNA repair seems frightening, there are ways to specifically target cancer cells:

We can use drugs to switch off another important DNA repair system. This leads to so much genetic damage that the cell is unable to survive. Healthy cells, on the other hand, which have all their systems repair, do not mind these drugs. "

Dr. Aurélie Ernst, Lead Author

Drugs called PARP inhibitors are already clinically approved agents that have a key to DNA repair and chromotropic disruption, it may be possible to treat them with PARP inhibitors in the future, preclinical and clinical tests.