ArticleCell research2017
Cryo-EM structure of human DNA-PK holoenzyme.
Article in Cell research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 116 citations in OpenAlex.
- Phase I crossover study of DNA-protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension.Clinical and translational science · 2023Trial
- Core NHEJ Factors Maintain Synapsis Across Diverse DNA End Structures.bioRxiv : the preprint server for biology · 2026Article
- DNA-PK driven nucleosome unwrapping enables NHEJ in chromatin.Nature communications · 2026Article
- Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation.RSC medicinal chemistry · 2026Review
- Multi-scale in-silico modelling to unveil structural requirements for DNA-PK inhibitors as radiosensitizers and MolSHAP based design of novel ligands.Journal of computer-aided molecular design · 2025Article
- DNA shape and epigenomics distinguish the mechanistic origin of human genomic structural variations.Nucleic acids research · 2025Article
- Unlocking the Therapeutic Potential of DNA-PKcs in Cancer: Comprehensive Insights into Mechanisms and Clinical Applications.Cancers · 2025Review
- Moesin silencing enhances the radiosensitivity of glioblastoma by inhibiting DNA damage repair via CD44/AKT1 signaling pathway.Discover oncology · 2025Article
- Homeodomain protein PRRX1 anchors the Ku heterodimers at DNA double-strand breaks to promote nonhomologous end-joining.Nucleic acids research · 2025Article
- DNA-PKcs, a player winding and dancing with RNA metabolism and diseases.Cellular & molecular biology letters · 2025Review
- The unique immune evasion mechanisms of the mpox virus and their implication for developing new vaccines and immunotherapies.Virologica Sinica · 2024Review
- Identification of 6-Anilino Imidazo[4,5-Journal of medicinal chemistry · 2024Article
- The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases.MedComm · 2024Review
- Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining.Nature communications · 2024Article
- New Discoveries on Protein Recruitment and Regulation during the Early Stages of the DNA Damage Response Pathways.International journal of molecular sciences · 2024Review
- Structural and functional basis of inositol hexaphosphate stimulation of NHEJ through stabilization of Ku-XLF interaction.Nucleic acids research · 2023Article
- How to fix DNA breaks: new insights into the mechanism of non-homologous end joining.Biochemical Society transactions · 2023Review
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13 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 Å resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal α-solenoid (∼2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA. DNA-PKcs and KU70/80 together form a DNA-binding tunnel, which cradles ∼30-bp DNA and prevents sliding inward of DNA-PKcs along with DNA duplex, suggesting a mechanism by which the broken DNA end is protected from unnecessary processing. Structural and biochemical analyses indicate that KU70/80 and DNA coordinately induce conformational changes of DNA-PKcs and allosterically stimulate its kinase activity. We propose a model for activation of DNA-PKcs in which allosteric signals are generated upon DNA-PK holoenzyme formation and transmitted to the kinase domain through N-terminal HEAT repeats and FAT domain of DNA-PKcs. Our studies suggest a mechanism for recognition and protection of broken DNA ends and provide a structural basis for understanding the activation of DNA-PKcs and DNA-PK-mediated NHEJ pathway.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.