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ケルン大学の研究者らは、ヒト、マウス、線虫細胞の DNA 修復機構を阻害し、それによって老化や病気の原因となる DREAM と呼ばれるタンパク質複合体を発見しました。 彼らは薬剤を用いてDREAM複合体を抑制することに成功し、DNA損傷に対する細胞の回復力を高め、老化やがんに対する新たな治療法の可能性を示唆したが、さらなる研究が必要である。

ケルン大学の研究者らは、タンパク質複合体がヒト細胞、マウス、線虫Caenorhabditis elegansのゲノム損傷の修復を妨げていることを発見した。 さらに、この複合体を薬剤で阻害することに初めて成功した。

「体の細胞内のいわゆるDREAM複合体を抑制すると、さまざまな修復メカニズムが作動し、これらの細胞があらゆる種類の病気に対して非常に回復力を持ちます。[{” attribute=””>DNA damage,” said Professor Dr. Björn Schumacher, Director of the Institute for Genome Stability in Aging and Disease at the University of Cologne’s CECAD Cluster of Excellence in Aging Research.

DNA, which holds our genetic data, needs to be safeguarded carefully. However, it’s under constant threat due to environmental factors or our normal metabolism. Therefore, repairing DNA is vital for maintaining the stability of our genome and ensuring the proper functioning of our cells.

“Our findings for the first time allow us to improve DNA repair in body cells and to target the causes of aging and cancer development,” Schumacher added. Still, more research is needed until these results can be translated into new therapies for human patients. The study was published in Nature Structural & Molecular Biology.

DNA-damage leads to aging and disease

Our genetic material is passed on from generation to generation. That is why it is particularly well protected in our germ cells. Highly precise DNA repair mechanisms are at work there, ensuring that only very few changes in the genetic material are passed on to offspring. Thanks to DNA repair, our human genome has been passed on to us by our ancestors for two hundred thousand years. It has always ensured that the genetic information is preserved. DNA is also constantly repaired in our body cells, but only for the duration of the individual’s life.

Sometimes, children are born with faulty DNA repair systems, making them age more quickly and develop typical age-related diseases such as neuro-degradation and arteriosclerosis already in childhood. In some cases, they also have an extremely increased risk of cancer. These are all consequences of DNA damage not being properly repaired.

The DREAM complex prevents repairs

Schumacher and his team explored why body cells do not have the same repair mechanisms as germ cells. In experiments with the nematode C. elegans, they found out that the DREAM protein complex limits the quantity of DNA repair mechanisms in body cells: the complex attaches to the DNA’s construction plans containing instructions for the repair mechanisms. This prevents them from being produced in large quantities. Germ cells, however, do not have the DREAM complex. Hence, they naturally produce large quantities of DNA repair mechanisms.

Mammals also have a DREAM-complex

In further experiments with human cells in the laboratory (cell culture), the scientists showed that the DREAM complex functions in the same way in human cells. They were also able to override the DREAM complex with a pharmaceutical agent. “We were very pleased to see the same effect as we did in C. elegans. The human cells were much more resilient towards DNA damage after treatment,” said Arturo Bujarrabal, a postdoc in Schumacher’s team and lead author of the study. Treatment with the DREAM complex inhibitor also showed amazing effects in mice: The DNA in the retina of mice could be repaired and the function of the eye was preserved. The test was carried out in mice that, like some patients, age prematurely and show a typical degeneration of the eye’s retina.

DNA-damage in space

Genome damage also plays a major role in manned spaceflight because of the extremely high radiation in space. A longer stay in space without improved DNA repair is hardly imaginable. Schumacher sums up: “Therapies that target and improve this newly discovered master regulator of DNA repair could reduce the risk of cancer because genes remain intact.” In addition, the risk of age-related diseases would be reduced because cells can only fulfill their function with an intact genome.

Reference: “The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities” by Arturo Bujarrabal-Dueso, Georg Sendtner, David H. Meyer, Georgia Chatzinikolaou, Kalliopi Stratigi, George A. Garinis, and Björn Schumacher, 23 March 2023, Nature Structural & Molecular Biology.
DOI: 10.1038/s41594-023-00942-8

The study was carried out at the Institute for Genome Stability in Aging and Disease of the University of Cologne’s CECAD Cluster of Excellence in Aging Research.

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