Self-damage to one’s own DNA increases the resistance of cancer cells to therapy – Human – Science and Technology

Commonly used radiation therapy kills cancer cells by causing extensive DNA damage in irradiated tissue. An international team, including several researchers from the Institute of Molecular Genetics of the Academy of Sciences of the Slovak Republic, has now revealed an unexpected strategy for how radiation-induced cancer cells are avoided – they themselves are further damaged.

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The illustration shows the function of a CAD enzyme that specifically damages DNA.

He published the study Science. DNA damage in human cells occurs naturally and is effectively repaired by a large number of DNA repair pathways. However, this process takes time. The dependence of cancer cells on rapid uncontrolled cell division therefore makes them unable to cope with the major DNA damage caused by high doses of radiation. Radiation therapy thus effectively kills tumor cells.

Despite the general success of radiation, tumors often return. The mechanisms by which tumor cells manage to avoid cell death after lethal doses of radiation are not well known, and therefore resistance to radiation therapy remains a major challenge for effective clinical control of tumors.

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Self-harm against death

A team of scientists from Denmark, the Czech Republic, Sweden, Canada and Switzerland, coordinated by Claus Storgaard Sørensen of the Biotech Research and Innovation Center, University of Copenhagen in Denmark, found that in response to radiation, tumor cells can activate endogenous nuclease CAD enzyme, which breaks down nucleic acids (including DNA) throughout the genome. While persistent DNA damage is generally bad for a cell, an international research team has shown that once radiation therapy causes initial DNA damage, cancer cells cause further DNA breaks themselves. This effectively suspends their division program and cell cycle at the so-called G2 checkpoint before cell division begins, giving them time to repair the remaining DNA damage.

This very surprising and somewhat intuitive strategy of adding targeted DNA breaks improves the chances of cancer cells of the lethal dose of radiation surviving. They can be compared e.g. to soldiers in the war who wound themselves so that they cannot be sent into battle.

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He explains the mechanism more specifically Jiří Bártek from the Institute of Molecular Genetics AS CR (IMG AS CR), one of the leading authors of the research: “While normal cells usually interrupt their division cycles in the so-called G1 phase checkpoint, this mechanism is mostly defective in cancer cells. Therefore, the main way to prevent catastrophic cell division with damaged chromosomes that would kill the dividing cells is to stay in the second G2 checkpoint just before the cells start to divide. Many defects caused by CAD “tell” tumor cells to wait until they repair the more dangerous DNA breaks caused by radiotherapy. “

Blocking to enhance treatment

In addition, the authors found that this phenomenon is specific for cancer cells. Loss of CAD activity causes cancer cells (against normal cells) to be susceptible to damage caused by radiation. “This unexpected new mechanism really indicates how cancer cells can adapt to radiation-induced DNA damage and thus become more resistant to radiotherapy,” explain Pavel Janščák and Václav Urban from IMG AS SR, who participated in this discovery and are co-authors of the scientific article. .

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Taken together, these findings shed light on a cancer-specific survival mechanism. This could be targeted and used in the future to increase the vulnerability of tumor cells to genotoxic cancer treatment. The study also showed that experimental blockade of CAD function made tumor cells (unlike normal, healthy cells) more sensitive to radiation, suggesting how this new knowledge could be used to improve radiotherapy outcomes in the future.


Source: Pravda – Veda a technika by vat.pravda.sk.

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