2023-09-06 17:05:51
Ultraviolet rays, alcohol, tobacco, hereditary predispositions, spontaneous mutations… many factors constantly damage our genome. Among these lesions, the sure breaks which affect both DNA strands simultaneously are the most deleterious. Our body constantly repairs this damage through several repair systems, including homologous recombination. However, when these mechanisms are defective (for example due to a genetic mutation), they can be at the origin of the appearance of cancer. Thus, the proven correlation between homologous recombination defects and the aggressiveness of cancers or their resistance to current chemotherapies underlines the crying need for new targeted anti-cancer therapies.
A new major player in DNA repair: PolꝊ
In recent years, a new player in DNA repair (polymerase theta or PolꝊ) has been identified as a therapeutic hope in the treatment of these cancers.
The “Alternative DNA repair mechanisms in cancers” team led by Dr Raphaël Ceccaldi, Inserm researcher at the Institut Curie, has just elucidated the mechanism of action of this polymerase and the reason why this enzyme is essential for the development of breast and ovarian cancers.
For the first time, scientists have shown that PolꝊ intervenes where other DNA repair pathways do not work. While the dogma was that DNA repair was impossible during cell division of cells (when DNA is extremely compacted), the Institut Curie team demonstrated that PolꝊ is specifically active during mitosis when other repair actors are ineffective.
Genome integrity strongly conserved thanks to PolꝊ
Thanks to a collaboration with the team of Dr Sophie Zinn-Justin, researcher at the CEA (Laboratory of Structural Biology and Radiobiology), the researchers went even further: they demonstrated that, in order to repair DNA, PolꝊ had to be activated by an enzyme present specifically during cell division. Moreover, the mechanisms allowing this activation of PolꝊ seem to have been extremely conserved during evolution. This suggests that they are playing a important role in maintaining genome stability necessary for the development of eukaryotic organisms.
PolꝊ (green) marks DNA breaks (H2AX, red) at the level of mitotic chromosomes (DAPI, blue) Scale 5μM © DR
A therapeutic hope in breast and ovarian cancers
Dr Raphaël Ceccaldi’s team has also demonstrated that inhibition of PolꝊ during cell division by mitosis prevents proper DNA repair and consequently leads to cancer cell death. With nearly half of breast and ovarian cancers showing defects in DNA repair by homologous recombination, this step is therefore a major point of attention in the fight once morest these cancers. Elucidating the molecular mechanisms governing the use and regulation of de PolꝊ might ultimately lead to the development of new therapeutic targets for the treatment of these cancers.
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