Dimers of DNA-PK create a stage for DNA double-strand break repair.

Amanda K Chaplin, Steven W Hardwick, Shikang Liang, Antonia Kefala Stavridi, Ales Hnizda, Lee R Cooper, Taiana Maia De Oliveira, Dimitri Y Chirgadze, Tom L Blundell

Nature structural & molecular biology 2021 Jan

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DNA double-strand breaks are the most dangerous type of DNA damage and, if not repaired correctly, can lead to cancer. In humans, Ku70/80 recognizes DNA broken ends and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form DNA-dependent protein kinase holoenzyme (DNA-PK) in the process of non-homologous end joining (NHEJ). We present a 2.8-Å-resolution cryo-EM structure of DNA-PKcs, allowing precise amino acid sequence registration in regions uninterpreted in previous 4.3-Å X-ray maps. We also report a cryo-EM structure of DNA-PK at 3.5-Å resolution and reveal a dimer mediated by the Ku80 C terminus. Central to dimer formation is a domain swap of the conserved C-terminal helix of Ku80. Our results suggest a new mechanism for NHEJ utilizing a DNA-PK dimer to bring broken DNA ends together. Furthermore, drug inhibition of NHEJ in combination with chemo- and radiotherapy has proved successful, making these models central to structure-based drug targeting efforts.

Citation

Amanda K Chaplin, Steven W Hardwick, Shikang Liang, Antonia Kefala Stavridi, Ales Hnizda, Lee R Cooper, Taiana Maia De Oliveira, Dimitri Y Chirgadze, Tom L Blundell. Dimers of DNA-PK create a stage for DNA double-strand break repair. Nature structural & molecular biology. 2021 Jan;28(1):13-19