Thursday , June 17 2021

Incorrect DNA repair triggers chromosomal chaos



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

By Novikov AlekseyNovikov Aleksey | Shutterstock

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

Just a few years ago, researchers at the same research center reported that in a particularly aggressive form of brain tumor in childhood there was an unprecedented chaos in the cell nuclei.

Sections of chromosomes were broken on multiple points and incorrectly mounted again, while other sections were incorrectly copied or incorporated.

These events, which researchers refer to as "chromotrips", had not seen before and differed from the genetic defects previously identified genetic defects.

Chromotripsis occurs in approximately 20-30% of all cancers, but up to 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 some genetic repair systems as one of the reasons.

The team studied a mouse model where the tools used by neural precursor cells to repair broken DNA had been genetically disconnected. As a result, the animals developed malignant brain tumors that exhibited a high rate of chromotrips.

In addition, chromotrips almost always occurred in conjunction with additional copies of the carcinogenic Myc oncogene.

If the DNA repair is defective and Myc still 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 the failed delivery and the resulting catastrophic chromosomal events also concern melanoma, brain tumors and breast cancer in humans and that Myc oncogen is again involved.

Ernst says that although the chromosome chaos caused by failed DNA repair seems scary, there is a way to specifically target cancer cells with such defects:

We can use drugs to turn off another important DNA repair system. This leads to so much genetic damage that the cell can not survive. Hefty cells, on the other hand, who have all their repair systems do not care about these drugs. "

Dr. Aurélie Ernst, Lead Author

Medicines called PARP inhibitors are already clinically approved agents that block a key DNA repair system and Ernst says that if the genetic material in a tumor exhibits chromotrips, it may be possible to treat them with PARP inhibitors in the future, although this should require confirmation in preclinical and clinical tests.

sources:

Defective DNA damage repair leads to chaos in the genome.

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nature Communications. 12th November 2018.


Source link