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Ku, a key protein in resistance of cancer cells to radiotherapy

An I2BC team identified by crystallography the first steps in the assembly of the DNA double strand break repair complex.

Radiotherapy is used in almost half of cancer treatments. The radiations generate DNA double strand breaks, which lead to cell death. However, some tumor cells can escape this by repairing breaks. Identifying the partners involved in repair and understanding their mode of action would increase the efficiency of radiotherapy by inhibiting repair mechanisms.
In irradiated cells, a ring-shaped protein called Ku very quickly encircles the ends of the double-stranded DNA breaks and recruits several protein partners to repair the DNA strands.
The team’s work identified the contact areas between Ku and two of its partners, APLF and XLF, and demonstrated that a modification of the contact areas would alter DNA repair and cell survival in post-irradiation.
These contact areas are promising new therapeutic targets, and the discovery of inhibitors of repair machinery assembly in tumor cells could increase their sensitivity to radiation therapy.

The Ku-XLF complex
The Ku-XLF complex
Crystal structure of the molecular complex (Ku : magenta, XLF : green)

This work is the result of a collaboration with teams from Toulouse, Marseille, Villejuif, the Synchrotron Soleil, and as well as Germany, Great Britain and the United States.

More information :
XLF and APLF bind to Ku80 on two remote sites to ensure repair by non-homologous end-joining,
Nemoz C, Ropars V, Frit P, Gontier A, Drevet P, Yu J, Guerois R, Pitois A, Comte A, Delteil C, Barboule B, Legrand P, Baconnais S, Yin Y, Tadi S, Barbet-Massin E, Berger I, Le Cam E, Modesti M, Rothenberg E, Calsou P & Charbonnier, JB
Nature Structural & Molecular Biology (2018) 25 : 971–980

Contact :
Jean-Baptiste Charbonnier

par Communication - publié le