ArticleProgress in biophysics and molecular biology2021
Visualizing functional dynamicity in the DNA-dependent protein kinase holoenzyme DNA-PK complex by integrating SAXS with cryo-EM.
Article in Progress in biophysics and molecular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- RNA sculpting by the primordial Helix-clasp-Helix-Strand-Loop (HcH-SL) motif enforces chemical recognition enabling diverse KH domain functions.The Journal of biological chemistry · 2025Review
- Secrets of DNA-PKcs beyond DNA repair.NPJ precision oncology · 2024Review
- Human DNA-dependent protein kinase activation mechanism.Nature structural & molecular biology · 2023Article
- Combining small angle X-ray scattering (SAXS) with protein structure predictions to characterize conformations in solution.Methods in enzymology · 2023Article
- Measuring the Radius of Gyration and Intrinsic Flexibility of Viral Proteins in Buffer Solution Using Small-Angle X-ray Scattering.ACS measurement science au · 2022Article
- Universally Accessible Structural Data on Macromolecular Conformation, Assembly, and Dynamics by Small Angle X-Ray Scattering for DNA Repair Insights.Methods in molecular biology (Clifton, N.J.) · 2022Article
- X-ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for DNA double-strand break repair impacting cell and cancer biology.Protein science : a publication of the Protein Society · 2021Review
- Uncovering DNA-PKcs ancient phylogeny, unique sequence motifs and insights for human disease.Progress in biophysics and molecular biology · 2021Article
- DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy.Signal transduction and targeted therapy · 2021Review
- An atypical BRCT-BRCT interaction with the XRCC1 scaffold protein compacts human DNA Ligase IIIα within a flexible DNA repair complex.Nucleic acids research · 2021Article
- Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy.Frontiers in immunology · 2021Review
- Structural insights into the role of DNA-PK as a master regulator in NHEJ.Genome instability & disease · 2021Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Assembly of KU and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at DNA double strand breaks (DSBs) forms DNA-PK holoenzyme as a critical initiating step for non-homologous end joining (NHEJ) repair of DSBs produced by radiation and chemotherapies. Advanced cryo-electron microscopy (cryo-EM) imaging together with breakthrough macromolecular X-ray crystal (MX) structures of KU and DNA-PKcs recently enabled visualization of the ∼600 kDa DNA-PK assembly at near atomic resolution. These important static structures provide the foundation for definition and interpretation of functional movements crucial to mechanistic understanding that can be tested through solution state structure analysis. We herein therefore leverage Cryo-EM and MX structures for the interpretation of synchrotron small-angle X-ray scattering (SAXS) data on DNA-PK conformations in solution to inform the structural mechanism for NHEJ initiation. SAXS, which measures thermodynamic solution-state conformational states and assemblies outside of cryo- and solid-state conditions, unveils the inherent flexibility of KU, DNA-PKcs and DNA-PK. The combined structural measurements reveal mobility of KU80 C-terminal region (KU80CTR), motion/plasticity of HEAT (DNA-PKcs Huntingtin, Elongation Factor 3, PP2 A, and TOR1) regions, allosteric switching upon DNA-PKcs autophosphorylation, and dimeric arrangements of DNA-PK assembly. Importantly, the results uncover displacement of the N-terminal HEAT domain during autophosphorylation as suitable for a regulated release mechanism of DNA-PKcs from DNA-PK to control unproductive access to toxic and mutagenic DNA repair intermediates. These integrated analyses show that the marriage of SAXS with cryo-EM leverages the strengths of both techniques to enable assessment of functional conformations and flexibility defining atomic-resolution molecular mechanisms for DSB repair.
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