Understanding the structure and role of DNA-PK in NHEJ: How X-ray diffraction and cryo-EM contribute in complementary ways.
Progress in biophysics and molecular biology
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Wu, Q., Liang, S., Ochi, T., Chirgadze, D., Huiskonen, J. T., & Blundell, T. (2019). Understanding the structure and role of DNA-PK in NHEJ: How X-ray diffraction and cryo-EM contribute in complementary ways.. Progress in biophysics and molecular biology, 147 26-32. https://doi.org/10.1016/j.pbiomolbio.2019.03.007
DNA double-strand breaks (DSBs), generated by ionizing radiation, reactive oxygen species and DNA replication across nicks, are the most severe DNA damage in eukaryotic cells. Non-Homologous End Joining repairs DNA double-strand breaks directly without a template and so can take place at any point in the cell cycle. Ku70/80 heterodimers rapidly assemble around broken DNA ends, allowing DNA-PKcs, the catalytic subunit of DNA-dependent protein kinase, to be recruited and facilitating synapsis of broken DNA ends. This then provides a stage for end-processing and ligation. Here we review progress leading in 2017 to the medium resolution X-ray structure of DNA-PKcs, a single polypeptide chain of 4128 amino acids. This was followed quickly by chain tracing of cryo-EM structures of DNA-PKcs in complex with Ku and DNA. We discuss how combination of structural information from X-ray and cryo-EM studies can produce a working model for complex multicomponent molecular assemblies such as those found in DNA-double-strand-break repair.
Animals, Humans, Cryoelectron Microscopy, Crystallography, X-Ray, DNA-Activated Protein Kinase, DNA End-Joining Repair, Protein Domains
WELLCOME TRUST (200814/Z/16/Z)
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External DOI: https://doi.org/10.1016/j.pbiomolbio.2019.03.007
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291675
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/