DNA REPAIR: DNA‐PKcs structure suggests an allosteric mechanism modulating DNA double‐strand break repair

Activating DNA repair DNA double-strand breaks must be repaired efficiently to avoid cell death or cancer. The break ends can either be directly ligated by nonhomologous end joining (NHEJ) or more accurately repaired by homologous recombination that uses information from the sister chromatid. Sibanda et al. present a high-resolution x-ray structure of a key component of the DNA repair machinery, the DNA-dependent kinase catalytic subunit (DNA-PKcs), bound to a C-terminal peptide of Ku80. The structure suggests that Ku80 presents the DNA ends for repair to a DNA-PKcs dimer and that activity is modulated by interactions between the monomers. Binding of either Ku80 or BRCA1, which may compete for the same binding site on DNA-PKcs, could provide a switch between NHEJ and homologous recombination. Science, this issue p. 520 A crystal structure shows how components of the nonhomologous end-joining machinery modulate kinase activation in DNA repair. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128–amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation. The location of KU80ct194 in the vicinity of the breast cancer 1 (BRCA1) binding site suggests competition with BRCA1, leading to pathway selection between NHEJ and homologous recombination.