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Structural biology of DNA repair: spatial organisation of the multicomponent complexes of nonhomologous end joining.

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Ochi, Takashi 
Sibanda, Bancinyane Lynn 
Wu, Qian 
Chirgadze, Dimitri Y 
Bolanos-Garcia, Victor M 


Nonhomologous end joining (NHEJ) plays a major role in double-strand break DNA repair, which involves a series of steps mediated by multiprotein complexes. A ring-shaped Ku70/Ku80 heterodimer forms first at broken DNA ends, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) binds to mediate synapsis and nucleases process DNA overhangs. DNA ligase IV (LigIV) is recruited as a complex with XRCC4 for ligation, with XLF/Cernunnos, playing a role in enhancing activity of LigIV. We describe how a combination of methods-X-ray crystallography, electron microscopy and small angle X-ray scattering-can give insights into the transient multicomponent complexes that mediate NHEJ. We first consider the organisation of DNA-PKcs/Ku70/Ku80/DNA complex (DNA-PK) and then discuss emerging evidence concerning LigIV/XRCC4/XLF/DNA and higher-order complexes. We conclude by discussing roles of multiprotein systems in maintaining high signal-to-noise and the value of structural studies in developing new therapies in oncology and elsewhere.



0601 Biochemistry and Cell Biology, Biomedical, Cancer, Genetics, Generic Health Relevance, 1.1 Normal biological development and functioning

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J Nucleic Acids

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Wellcome Trust (079281/Z/06/Z)