Many anticancer treatments eliminate tumor cells by breaking their DNA. Some cells survive these fractures by repairing them, which limits the effectiveness of these treatments. Researchers at the Institute of Pharmacology and Biology structural discovered the operation of one of the first key steps of this repair. Their results, which revealed new potential therapeutic targets for the treatment of cancers, are published in the journal Nature Communications.

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Ku is normally removed from the end of breaks induced by camptothecin through the activity of several nucleases (left panels). When these nucleases are inactive (right panels), Ku accumulates on the breaks induced by camptothecin, blocking their repair and leads to the death cell. Junction of Extremities Not Counterpart (JENH) is a very effective way of repairing DNA breaks; it is to pick up together the two ends of the break.

To do this, a very abundant protein, ring-shaped, the Ku protein (pronounced Kou!), Detects and recovers very quickly each end of the break, and then serves as the point of attachment to the other proteins in this pathway repair.  Among the treatments anticancer camptothecin and derivatives thereof, lead to specific DNA breaks, which have only one end. In the absence of a second end, the rebinding by JENH is not possible and DNA breaks generated by camptothecin must be repaired by other means, homologous recombination.

This work also established that other proteins that cut DNA, nucleases, remove subsequently the protein Ku these breaks. These proteins work in a coordinated way by cutting the DNA end carrying Ku while modifying this end to prevent Ku reattach it.

Finally, this work shows that when this mechanism is inhibited, the persistence of Ku blocks the assembly of repair proteins by Homologous Recombination which in absence of adequate break repair, leads to cell death.  These processes characterization work fundamental repair of DNA breaks lead to the identification of complex and mechanisms required for cell survival in the presence of some anticancer agents.