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. 2021 Jan;28(1):13-19.
doi: 10.1038/s41594-020-00517-x. Epub 2020 Oct 19.

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

Amanda K Chaplin #  1 , Steven W Hardwick #  2 , Shikang Liang  1 , Antonia Kefala Stavridi  1 , Ales Hnizda  1 , Lee R Cooper  2 , Taiana Maia De Oliveira  3 , Dimitri Y Chirgadze  2 , Tom L Blundell  4
Affiliations

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

Amanda K Chaplin et al. Nat Struct Mol Biol. 2021 Jan.

Abstract

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.

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References

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