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DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair

DOI: 10.1126/science.aak9654 DOI Help

Authors: Bancinyane L. Sibanda (University of Cambridge) , Dimitri Y. Chirgadze (University of Cambridge) , David B. Ascher (University of Cambridge) , Tom L. Blundell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 355 , PAGES 520 - 524

State: Published (Approved)
Published: February 2017
Diamond Proposal Number(s): 9007 , 9537

Abstract: 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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility

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