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-Structure paper
Title | Dimers of DNA-PK create a stage for DNA double-strand break repair. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 28, Issue 1, Page 13-19, Year 2021 |
Publish date | Oct 19, 2020 |
Authors | 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 / |
PubMed 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 ...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. |
External links | Nat Struct Mol Biol / PubMed:33077952 |
Methods | EM (single particle) |
Resolution | 3.24 - 7.24 Å |
Structure data | EMDB-11185, PDB-6zfp: EMDB-11211, PDB-6zh2: EMDB-11213, PDB-6zh4: EMDB-11215, PDB-6zh6: EMDB-11216, PDB-6zh8: EMDB-11217, PDB-6zha: EMDB-11219, PDB-6zhe: |
Source |
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Keywords | DNA BINDING PROTEIN / Kinase / DNA-PKcs / NHEJ / DNA-repair / DNA-PK / Ku80 / Ku70/80 |