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Ku at single-ended DNA breaks: remain or break-exit ?

Several current anticancer treatments kill cancer cells by inducing DNA double-strand breaks, a highly toxic DNA damage in which both strands of the DNA molecule are broken. Some cancer cells manage to survive these breaks thanks to DNA repair mechanisms. Researchers from the Institut de Pharmacologie et de Biologie Structurale deciphered one of the key initial step of these repair mechanisms. This work, published in Nature Communications, also identified several potential drug targets for anticancer treatments.

 

A very efficient repair pathway for DNA double-strand breaks is Non-Homologous End Joining (NHEJ) that consists in gluing together the two DNA ends generated at the break. This mechanism is initiated by Ku, an abundant ring-shaped protein. Ku rapidly recognizes and accommodates DNA ends through its cavity and then creates an assembly site for the rest of the NHEJ proteins. The anticancer agent camptothecin and its derivatives create specific DNA breaks that have only one DNA end, called “single-ended”. NHEJ, which needs two ends to function, cannot repair these breaks that have to be repaired by another DNA repair mechanism, Homologous Recombination.

In a recent publication in Nature Communications, the team of Patrick Calsou at IPBS established that despite single-ended breaks generated by camptothecin are not repaired by NHEJ, they are initially recognized by the NHEJ protein Ku. They demonstrated that the coordinated CtIP and MRE11 nuclease activities cleave the DNA ends carrying Ku while modifying these ends to block subsequent Ku binding and priming them for repair by Homologous Recombination. They show that the kinase ATM activates this mechanism by phosphorylating CtIP. Finally, they established that Ku persistence resulting of inhibition of this mechanism blocks the recruitment of Homologous Recombination proteins while inducing toxic DNA repair events in proliferating cells treated with camptothecin.

While deciphering a complex mechanism essential for cell survival to camptothecin, this work also identified interesting potential drug targets against which Patrick Calsou’s lab is currently isolating new inhibitors that could be used to sensitize cancer cells to current anticancer treatments.

 

This work stems from a collaboration with the Steve Jackson’s lab in Cambridge and was made possible thanks to funding from La Ligue contre le Cancer (Equipe Labellisée 2013).

 

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Coordination of CtIP and Mre11 nuclease activities release Ku from single-ended DNA double-strand breaks. A. Depletion of CtIP leads to toxic Ku persistence (green dots) at breaks generated by camptothecin (visualized using the gH2AX DNA double-strand break marker, red dots). B. Model depicting the main findings of the paper.

 

Reference:

Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks. Pauline Chanut†, Sébastien Britton†*, Julia Coates, Stephen P. Jackson* and Patrick Calsou*. Nature Communications. 10.1038/NCOMMS12889 
† Pauline Chanut & Sébastien Britton contributed equally; * Corresponding authors

 

Contact:

Patrick Calsou ; Institut de Pharmacologie et de Biologie Structurale ; 205 route de Narbonne ; 31077 Toulouse ; tel. : 0561175970 ; email : Patrick.Calsou@ipbs.fr

Sébastien Britton ; Institut de Pharmacologie et de Biologie Structurale ; 205 route de Narbonne ; 31077 Toulouse ; tel. : 0561175907 ; email : Sebastien.Britton@ipbs.fr