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Structure of an activated DNA-PK and its implications for NHEJ.

Chen X, Xu X, Chen Y, Cheung JC, Wang H, Jiang J, de Val N, Fox T, Gellert M, Yang W
Mol Cell 81 801-810.e3 (2021)
Related entries: 7k10, 7k11, 7k17, 7k19, 7k1b, 7k1j, 7k1k, 7k1n

Cited: 54 times
EuropePMC logo PMID: 33385326

Abstract

DNA-dependent protein kinase (DNA-PK), like all phosphatidylinositol 3-kinase-related kinases (PIKKs), is composed of conserved FAT and kinase domains (FATKINs) along with solenoid structures made of HEAT repeats. These kinases are activated in response to cellular stress signals, but the mechanisms governing activation and regulation remain unresolved. For DNA-PK, all existing structures represent inactive states with resolution limited to 4.3 Å at best. Here, we report the cryoelectron microscopy (cryo-EM) structures of DNA-PKcs (DNA-PK catalytic subunit) bound to a DNA end or complexed with Ku70/80 and DNA in both inactive and activated forms at resolutions of 3.7 Å overall and 3.2 Å for FATKINs. These structures reveal the sequential transition of DNA-PK from inactive to activated forms. Most notably, activation of the kinase involves previously unknown stretching and twisting within individual solenoid segments and loosens DNA-end binding. This unprecedented structural plasticity of helical repeats may be a general regulatory mechanism of HEAT-repeat proteins.

Reviews - 7k0y mentioned but not cited (1)

  1. Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy. Matsumoto Y. Int J Mol Sci 23 4264 (2022)

Articles - 7k0y mentioned but not cited (6)

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  2. Structure of an activated DNA-PK and its implications for NHEJ. Chen X, Xu X, Chen Y, Cheung JC, Wang H, Jiang J, de Val N, Fox T, Gellert M, Yang W. Mol Cell 81 801-810.e3 (2021)
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Articles citing this publication (30)

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  4. DNA-PK promotes DNA end resection at DNA double strand breaks in G0 cells. Fowler FC, Chen BR, Zolnerowich N, Wu W, Pavani R, Paiano J, Peart C, Chen Z, Nussenzweig A, Sleckman BP, Tyler JK. Elife 11 e74700 (2022)
  5. Physical ARTEMIS:DNA-PKcs interaction is necessary for V(D)J recombination. Niewolik D, Schwarz K. Nucleic Acids Res 50 2096-2110 (2022)
  6. The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened. Cisneros-Aguirre M, Lopezcolorado FW, Tsai LJ, Bhargava R, Stark JM. Nat Commun 13 3662 (2022)
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  9. Structural analysis of the basal state of the Artemis:DNA-PKcs complex. Watanabe G, Lieber MR, Williams DR. Nucleic Acids Res 50 7697-7720 (2022)
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  13. Structural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus. Rivera-Calzada A, Arribas-Bosacoma R, Ruiz-Ramos A, Escudero-Bravo P, Boskovic J, Fernandez-Leiro R, Oliver AW, Pearl LH, Llorca O. Nat Commun 13 7062 (2022)
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  15. Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer? Lazo PA. Cancers (Basel) 14 4050 (2022)
  16. The mechanisms of human lymphoid chromosomal translocations and their medical relevance. Liu D, Lieber MR. Crit Rev Biochem Mol Biol 57 227-243 (2022)
  17. ATM phosphorylates the FATC domain of DNA-PKcs at threonine 4102 to promote non-homologous end joining. Lu H, Zhang Q, Laverty DJ, Puncheon AC, Augustine MM, Williams GJ, Nagel ZD, Chen BPC, Davis AJ. Nucleic Acids Res 51 6770-6783 (2023)
  18. LINC01419 Promotes the Proliferation of Hepatoma Cells by Recruiting XRCC5 and Regulating Its Phosphorylation to Repair DNA Damage. Liu P, Zhang X, Fu Q, Liu C, Luo Q, Yu P, Chen S, Zhang H, Qin T. Dis Markers 2022 9313680 (2022)
  19. Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease. Chandra AN, Saravanabavan S, Rangan GK. Int J Mol Sci 22 10512 (2021)
  20. Proximal binding of dCas9 at a DNA double strand break stimulates homology-directed repair as a local inhibitor of classical non-homologous end joining. Feng YL, Liu SC, Chen RD, Sun XN, Xiao JJ, Xiang JF, Xie AY. Nucleic Acids Res 51 2740-2758 (2023)
  21. Requirement of WDR70 for POLE3-mediated DNA double-strand breaks repair. Mao X, Wu J, Zhang Q, Zhang S, Chen X, Liu X, Wei M, Wan X, Qiu L, Zeng M, Lei X, Liu C, Han J. Sci Adv 9 eadh2358 (2023)
  22. Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress. Howes AC, Perisic O, Williams RL. Sci Adv 9 eadi8291 (2023)
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