discovery of new DNA repair system brings hope

discovery of new DNA repair system brings hope

France –French researchers have elucidated the mechanisms of action of polymerase theta (PolꝊ), which is involved in DNA repair. Published in Naturetheir results pave the way for the development of new therapeutic targets for the treatment of cancer, in particular breast and ovarian cancer. [1].

“It is through understanding such mechanisms that we can develop new ways to prevent cancer. Our discoveries about the role and function of polymerase theta in maintaining genome integrity allow us to look at new therapeutic prospects against cancer, especially breast and ovarian cancer,” says Dr. Rafael CecaldiInserm researcher and group leader at the Institut Curie.

Protein PolꝊ, capable of acting during cell division.

Our genome is constantly damaged by many factors, and among the damage caused, the most destructive are breaks that affect both strands of DNA at the same time. Our body continually repairs this damage using multiple repair systems, including homologous recombination. However, when these mechanisms fail (for example, due to a genetic mutation), they can cause cancer.

This is the case with breast and ovarian cancer, almost half of which are associated with failure of biological DNA repair systems. Hence the interest in the discovery of researchers from the Institut Curie, Inserm and CEA, who reveal a hitherto unknown DNA repair mechanism involving the protein PolꝊ, which can act during cell division.

Because in fact, if the PolꝊ protein has been known since at least 2015, as evidenced by the publication in Nature published by Harvard researchers whose first author at the time was Rafael Cecaldi. [3] – the “Alternative Mechanisms of DNA Repair in Cancer” team, which is now headed by a scientist, has just discovered the mechanism of action of this polymerase. For the first time, researchers have shown that PolꝊ intervenes where other DNA repair pathways fail.

“Although the dogma has been that DNA repair is not possible during cell division (when DNA is extremely compacted), the researchers demonstrated that PolꝊ is active specifically during mitosis, when other repair players are ineffective,” the Institut Curie said in a press release.[3].

Development of new therapeutic targets becomes possible

Thanks to collaboration with the team Dr. Sophie Zinn-Justin, a researcher at the CEA (Structural Biology and Radiobiology Laboratory), the researchers went even further: they demonstrated that in order to repair DNA, PolꝊ must be activated by an enzyme present specifically during cell division. Moreover, the mechanisms mediating this activation of PolꝊ appear to have been extremely conserved throughout evolution. This suggests that they play an important role in maintaining genome stability necessary for the development of eukaryotic organisms.

Dr. Rafael Ceccaldi’s team also found the reason why this enzyme is necessary for the development of breast and ovarian cancer. Indeed, it has been demonstrated that inhibition of PolꝊ during cell division by mitosis prevents proper DNA repair and consequently leads to cancer cell death. Since nearly half of breast and ovarian cancers exhibit defects in DNA repair by homologous recombination, this step represents a key step in the fight against these cancers.

Elucidating the molecular mechanisms governing PolꝊ utilization and regulation may ultimately lead to the development of new therapeutic targets for the treatment of these cancers.

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