Affinage

PRKDC

DNA-dependent protein kinase catalytic subunit · UniProt P78527

Round 2 corrected
Length
4128 aa
Mass
469.1 kDa
Annotated
2026-04-28
130 papers in source corpus 47 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNA-PKcs (PRKDC) is a PI3K-family serine/threonine protein kinase that serves as the catalytic core of the DNA-PK holoenzyme, orchestrating non-homologous end joining (NHEJ), V(D)J recombination, checkpoint signaling, innate immune DNA sensing, and ribosome biogenesis. Recruited to DNA double-strand break ends by the Ku70/Ku80 heterodimer via the Ku80 C-terminal domain, DNA-PKcs undergoes DNA-end-structure-dependent autophosphorylation at the ABCDE cluster, triggering a gross conformational rearrangement that switches the enzyme from a DNA-end-protective to a processing-competent state, enabling Artemis nuclease recruitment and hairpin opening essential for V(D)J recombination and overhang processing (PMID:11955432, PMID:34936881, PMID:33385326). Beyond NHEJ, DNA-PKcs phosphorylates diverse substrates—including p53, ATM, RPA32/TopBP1, hnRNP-A1, FUS, SOX2, GOLPH3, Fis1, and glycolytic enzymes ALDOA/PKM2—thereby coordinating DNA damage checkpoints, telomere protection, replication fork reversal, Golgi dispersal, mitochondrial dynamics, and metabolic reprogramming (PMID:9363941, PMID:27939942, PMID:23897887, PMID:25999341, PMID:24485452, PMID:36130596, PMID:35290083, PMID:35078861). DNA-PKcs also functions in a Ku-dependent, NHEJ-independent pathway in which U3 snoRNA activates the kinase to promote 18S rRNA processing and hematopoiesis, and it mediates a STING-independent innate antiviral response to cytoplasmic DNA (PMID:32103174, PMID:31980485).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Establishing that a large catalytic subunit (DNA-PKcs) is activated by recruitment to DNA ends through physical interaction with Ku resolved the composition and activation mechanism of the DNA-PK holoenzyme.

    Evidence Biochemical fractionation, co-immunoprecipitation, DNA cross-linking, and in vitro kinase assays with purified components

    PMID:8422676

    Open questions at the time
    • No structural information on the DNA-PKcs–Ku interaction
    • In vivo relevance of DNA-end-dependent activation not yet demonstrated
  2. 1995 High

    Cloning of the DNA-PKcs cDNA placed it in the PI3K superfamily but demonstrated it is a protein kinase without lipid kinase activity, defining its catalytic identity.

    Evidence cDNA cloning, sequence analysis, and in vitro kinase assay comparing protein and lipid substrates

    PMID:7671312

    Open questions at the time
    • Substrate specificity beyond in vitro model substrates was unknown
    • No structural basis for why lipid kinase activity is absent
  3. 1997 High

    Identification of p53 (S15/S37) and c-Abl as DNA-PK substrates demonstrated that DNA-PKcs signals beyond DNA repair into cell survival and damage-response cascades, with reciprocal c-Abl phosphorylation providing the first evidence of feedback regulation.

    Evidence In vitro kinase assays with purified DNA-PK, co-immunoprecipitation, transactivation and IR-stimulated phosphorylation assays

    PMID:9109492 PMID:9363941

    Open questions at the time
    • Relative contribution of DNA-PKcs versus ATM/ATR to p53 S15 phosphorylation in vivo was unresolved
    • Physiological significance of c-Abl feedback on DNA-PK activity unclear
  4. 2002 High

    Reconstitution of the Artemis–DNA-PKcs complex demonstrated that DNA-PKcs-dependent phosphorylation activates Artemis endonuclease for hairpin opening and overhang processing, solving the molecular basis of coding-joint formation in V(D)J recombination and overhang trimming in NHEJ.

    Evidence Biochemical reconstitution with purified proteins, in vitro nuclease assays, and RAG hairpin opening assays

    PMID:11955432

    Open questions at the time
    • Structural basis of Artemis activation unknown
    • How autophosphorylation controls the protection-to-processing switch was unclear
  5. 2002 High

    Mouse genetic studies revealed that DNA-PKcs contributes to telomere length maintenance and end-fusion pathways, extending its role beyond canonical NHEJ.

    Evidence DNA-PKcs/Terc double-knockout mice with telomere length and cytogenetic analyses

    PMID:12426399

    Open questions at the time
    • Telomeric substrate of DNA-PKcs not identified
    • Whether DNA-PKcs acts through phosphorylation or end-protection at telomeres was unknown
  6. 2005 High

    Multiple advances resolved DNA-PKcs regulation and signaling: PP5 was identified as the first DNA-PKcs phosphatase; Ku80's C-terminal motif was shown to be necessary and sufficient for DNA-PKcs recruitment; and DNA-PKcs was placed in innate immune signaling via NF-κB/IKK activation and TLR9-independent Akt phosphorylation in response to CpG-DNA.

    Evidence Co-immunoprecipitation, in vitro phosphatase/kinase assays, Ku80 mutagenesis with laser microirradiation, DNA-PKcs-knockout macrophages with cytokine and Akt phosphorylation readouts

    PMID:11136976 PMID:14734805 PMID:15678105 PMID:15758953

    Open questions at the time
    • How PP5 is itself regulated in the DDR context was unknown
    • Full spectrum of innate immune targets of DNA-PKcs uncharacterized
  7. 2007 High

    Live-cell imaging showed that autophosphorylation does not govern initial DNA-PKcs recruitment but destabilizes its binding to DNA ends, establishing that the autophosphorylation-dependent release is a key regulatory step enabling downstream NHEJ.

    Evidence Laser-induced DSBs, FRAP, kinase-dead and phospho-site mutant DNA-PKcs in living cells

    PMID:17438073

    Open questions at the time
    • Which specific phospho-sites control release was not fully resolved
    • How release is coordinated with ligation complex assembly was unclear
  8. 2013 High

    A cell-free system showed that DNA-PKcs primes ATR/Chk1 activation by phosphorylating RPA32 and TopBP1 on gapped DNA structures, placing DNA-PKcs upstream of ATR at replication-associated DSBs and revealing cross-talk between NHEJ and ATR checkpoint pathways.

    Evidence Human cell-free extracts with defined DNA substrates, immunodepletion, in vitro kinase assays

    PMID:23897887

    Open questions at the time
    • In vivo validation of this specific RPA32/TopBP1 phosphorylation hierarchy was limited
    • Whether this pathway operates at all replication-born DSBs or only a subset was unknown
  9. 2015 High

    DNA-PKcs was shown to phosphorylate hnRNP-A1 during G2/M to promote the RPA-to-POT1 switch on telomeric overhangs, identifying the telomeric substrate of DNA-PKcs and providing a mechanism for cell-cycle-dependent telomere protection.

    Evidence In vitro kinase assay, phospho-site mutants, co-immunoprecipitation, telomere FISH, DNA damage focus analysis

    PMID:25999341

    Open questions at the time
    • Whether DNA-PKcs-hnRNP-A1 axis is the sole pathway for telomere protection during mitosis
    • Structural basis of hnRNP-A1 recognition by DNA-PKcs unknown
  10. 2016 High

    Direct phosphorylation of ATM by DNA-PKcs was shown to inhibit ATM kinase activity, establishing DNA-PKcs as a negative regulator of ATM and a molecular switch governing NHEJ versus HR pathway choice.

    Evidence In vitro kinase assay with purified ATM and DNA-PKcs, phospho-mimetic/blocking ATM mutants, DNA-PKcs inhibitor and genetic deletion in human cells

    PMID:27939942

    Open questions at the time
    • Whether this inhibition is constitutive or DNA-damage-phase-specific was unresolved
    • The full set of ATM phosphorylation sites targeted by DNA-PKcs not mapped
  11. 2017 High

    Crystal and cryo-EM structures of DNA-PKcs alone and in the holoenzyme revealed the three-unit architecture, the DNA-binding tunnel protecting ~30 bp, and allosteric conformational changes linking Ku80 binding and DNA engagement to kinase activation.

    Evidence X-ray crystallography (4.3 Å) and cryo-EM (5.8–6.6 Å) of DNA-PKcs ± Ku80 C-terminal peptide/KU70/80/dsDNA

    PMID:28154079 PMID:28652322 PMID:28840859

    Open questions at the time
    • Resolution insufficient for active-site chemistry details
    • No structure of autophosphorylated or substrate-bound states
  12. 2020 High

    Multiple discoveries broadened the functional landscape: high-resolution cryo-EM captured the inactive-to-active transition showing HEAT-repeat plasticity; hairpin DNA was shown to specifically stimulate ABCDE autophosphorylation; a Ku-dependent role in 18S rRNA processing via U3 snoRNA was uncovered; and a STING-independent antiviral innate immune pathway driven by DNA-PK was identified.

    Evidence Cryo-EM (3.2–3.7 Å), in vitro kinase assays with defined DNA structures, mouse knock-in models, RNA immunoprecipitation, ribosome profiling, phosphoproteomics, antiviral assays

    PMID:31980485 PMID:32103174 PMID:32716029 PMID:33385326

    Open questions at the time
    • How DNA-PK discriminates self from foreign DNA in the innate immune pathway is unclear
    • Whether rRNA-processing and NHEJ functions of DNA-PKcs are temporally or spatially segregated is unknown
  13. 2021 High

    Cryo-EM of autophosphorylated DNA-PK and the Artemis-bound complex revealed that ABCDE phosphorylation widens the DNA-binding groove to permit Artemis docking, while Artemis locks DNA-PK into a kinase-inactive state, defining a substrate-driven protection-to-processing switch.

    Evidence Cryo-EM of DNA-PK before/after autophosphorylation and with Artemis + hairpin DNA, in vitro hairpin opening assays

    PMID:34936881

    Open questions at the time
    • Kinetics of the conformational switch in vivo not measured
    • How other NHEJ factors (XRCC4/XLF/Lig4) integrate with this switch structurally
  14. 2022 High

    Several studies expanded DNA-PKcs substrates and functions: it promotes replication fork reversal independently of NHEJ; it phosphorylates Fis1-T34 to drive mitochondrial fission in kidney injury; it phosphorylates glycolytic enzymes ALDOA/PKM2 to regulate glycolysis in prostate cancer; and structural characterization of the basal Artemis–DNA-PKcs complex revealed mutually exclusive Artemis and XRCC4 binding.

    Evidence DNA fiber/EM of replication forks, Fis1-T34A knock-in mice, quantitative proteomics with metabolomics, cryo-EM of Artemis–DNA-PKcs complex, co-immunoprecipitation with peptide competition

    PMID:35078861 PMID:35290083 PMID:35801871 PMID:36130596

    Open questions at the time
    • Mechanism by which DNA-PKcs recognizes stalled replication forks is unknown
    • Physiological relevance of glycolytic enzyme phosphorylation outside prostate cancer is untested
    • Structural basis for mutual exclusivity of Artemis and XRCC4 binding at atomic resolution is lacking
  15. 2023 High

    Visualization of three additional DNA-PKcs dimeric transition states during NHEJ completed the structural cycle: autophosphorylation causes Ku and DNA-PKcs to rotate outward, exposing DNA ends for processing and promoting DNA-PKcs dissociation.

    Evidence Single-particle cryo-EM capturing pre-synaptic, synaptic, and post-autophosphorylation dimeric states

    PMID:37256947

    Open questions at the time
    • Full NHEJ synaptic complex including XRCC4–Lig4–XLF not yet captured at high resolution with DNA-PK
    • Transition-state kinetics and regulation by other factors in vivo remain unmeasured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how DNA-PKcs discriminates between self and foreign DNA in the STING-independent innate immune pathway; whether its rRNA-processing and NHEJ functions are spatially or temporally segregated; the structural basis of replication fork recognition; and the full regulatory cycle integrating all NHEJ synaptic components at atomic resolution.
  • No structural model of DNA-PKcs at stalled replication forks
  • Innate immune DNA-sensing mechanism not structurally resolved
  • Complete NHEJ synaptic complex with all factors not captured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3 GO:0140657 ATP-dependent activity 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 9 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-69306 DNA Replication 1 R-HSA-8953854 Metabolism of RNA 1
Partners
ABL1DCLRE1CHUWE1PPP5CRNF144ATP53XRCC5XRCC6
Complex memberships
Artemis–DNA-PKcs complexDNA-PK holoenzyme (DNA-PKcs/Ku70/Ku80)Small subunit processome (rRNA processing)

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 DNA-PK requires DNA ends for activation and is a multicomponent complex: Ku (a well-characterized autoimmune antigen) directs the catalytic ~350 kDa subunit (DNA-PKcs) to DNA via protein-protein interactions; Ku and DNA-PKcs were separated by fractionation and their association demonstrated by co-immunoprecipitation and DNA cross-linking. Biochemical fractionation, DNA cross-linking, co-immunoprecipitation, in vitro kinase assay Cell High 8422676
1995 Cloning of DNA-PKcs cDNA revealed it belongs to the phosphatidylinositol 3-kinase (PI3K) family; despite structural similarity to lipid kinases, DNA-PK phosphorylates proteins but shows no detectable lipid kinase activity in biochemical assays. cDNA cloning, sequence analysis, in vitro kinase assay (protein vs. lipid substrates) Cell High 7671312
1997 DNA-PK phosphorylates p53 at serines 15 and 37, and this phosphorylation reduces p53's interaction with its negative regulator MDM2 in vitro and in vivo, thereby relieving MDM2-mediated inhibition of p53 transactivation. In vitro kinase assay with purified DNA-PK, co-immunoprecipitation, transactivation assay Cell High 9363941
1997 DNA-PKcs constitutively interacts with the c-Abl tyrosine kinase; ionizing radiation stimulates this interaction and association with Ku. DNA-PK phosphorylates and activates c-Abl in vitro; conversely, c-Abl phosphorylates DNA-PKcs (but not Ku) in vitro, inhibiting DNA-PK complex formation with DNA. In vivo, c-Abl-dependent phosphorylation of DNA-PKcs occurs after irradiation. Co-immunoprecipitation, in vitro kinase assay, DNA-PK-deficient cells (functional rescue experiments) Nature High 9109492
1999 DNA-PKcs requires Mg2+, DNA ends, and Ku proteins for optimal in vitro activity; the minimal phosphorylation consensus for DNA-PK (and ATM/ATR) is S/TQ, with hydrophobic and negatively charged residues N-terminal to S/T as positive determinants and positively charged residues as negative determinants. DNA Ligase IV was identified as a specific in vitro substrate of DNA-PK. In vitro kinase assay, peptide library screening, substrate mutagenesis The Journal of biological chemistry High 10608806
2002 Artemis forms a stable complex with DNA-PKcs in the absence of DNA; upon complex formation, DNA-PKcs phosphorylates Artemis, which then acquires endonucleolytic activity on 5′ and 3′ overhangs and hairpins. The Artemis:DNA-PKcs complex can open hairpins generated by RAG, establishing the molecular basis for hairpin opening in V(D)J recombination and overhang processing in NHEJ. Biochemical reconstitution, in vitro kinase/nuclease assay, RAG hairpin opening assay Cell High 11955432
2002 DNA-PKcs has a functional role in telomere length maintenance: mice doubly deficient in DNA-PKcs and telomerase (Terc−/−/DNA-PKcs−/−) show accelerated telomere shortening compared with Terc−/− controls, and DNA-PKcs is essential for end-to-end fusions and apoptosis triggered by critically short telomeres. Mouse double-knockout genetics, telomere length analysis, cytogenetic analysis The EMBO journal High 12426399
2004 Protein phosphatase 5 (PP5) physically interacts with DNA-PKcs and dephosphorylates it with specificity at two functional autophosphorylation sites; both hypo- and hyperphosphorylation of DNA-PKcs at these sites increases radiation sensitivity, identifying PP5 as the first phosphatase for DNA-PKcs in DSB repair. Co-immunoprecipitation, in vitro phosphatase assay, radiation sensitivity assay Proceedings of the National Academy of Sciences of the United States of America High 14734805
2005 DNA-PKcs is required for activation of innate immunity by bacterial DNA and immunostimulatory oligodeoxynucleotides (ISS-ODN): DNA-PKcs−/− macrophages show defective IL-6 and IL-12 production; ISS-ODN activates DNA-PK, which in turn contributes to IKK and NF-κB activation, linking DNA repair machinery to innate immune signaling. DNA-PKcs knockout mouse macrophages, cytokine ELISA, in vitro kinase assay, IKK activity assay Cell High 11136976
2005 DNA-PKcs directly phosphorylates and activates Akt in response to CpG-DNA stimulation; in DNA-PKcs−/− macrophages, CpG-DNA-induced Akt phosphorylation is defective independent of TLR9. In vitro, purified DNA-PK phosphorylates recombinant Akt. Upon CpG-DNA stimulation, DNA-PKcs associates with Akt and triggers transient nuclear Akt translocation. DNA-PKcs knockout macrophages, in vitro kinase assay with purified proteins, co-immunoprecipitation The EMBO journal High 15678105
2005 Conserved C-terminal motifs in Ku80 are required for its interaction with DNA-PKcs and for efficient recruitment of DNA-PKcs to sites of DNA damage; disrupting this motif abrogates DNA-PKcs-mediated checkpoint signaling, establishing the Ku80 C-terminal domain as the physical linker that recruits DNA-PKcs to DNA damage sites. Mutational analysis, co-immunoprecipitation, laser microirradiation/focus formation, checkpoint signaling assays Nature High 15758953
2007 DNA-PKcs accumulates at DSB sites in a Ku80-dependent manner in vivo; kinase activity and autophosphorylation status do not influence initial recruitment but do regulate the stability of DNA-PKcs binding to DNA ends—impairing both results in maintained presence at unrepaired DSBs. Autophosphorylation thus facilitates NHEJ by destabilizing DNA-PKcs interaction with DNA ends. Laser-induced DSBs in living cells, live-cell imaging, FRAP, DNA-PKcs kinase-dead and phospho-site mutants The Journal of cell biology High 17438073
2007 DNA-PK phosphorylates a cluster of 13 Ser/Thr residues in the N-terminal transcriptional regulatory domain of Oct-1 after ionizing radiation; Ser/Thr→Ala substitutions eliminate IR-induced Oct-1 phosphorylation and abolish Oct-1's ability to rescue survival of irradiated Oct-1−/− fibroblasts, linking DNA-PK-dependent phosphorylation to a cell-survival pathway. In vitro phosphorylation, site-directed mutagenesis, Oct-1−/− MEF rescue assay, ChIP Oncogene High 17213819
2010 DNA-PKcs regulates the single-stranded DNA endonuclease activity of Artemis: purified Artemis alone has ssDNA endonuclease activity that is stimulated by DNA-PKcs; the divalent cation- and sequence-dependence of this activity is the same as the Artemis:DNA-PKcs dsDNA endonuclease, expanding the substrate range of the complex. In vitro nuclease assay with purified proteins, inhibitory antibodies, gel filtration DNA repair High 20117966
2010 DNA-PKcs cooperates with WRN helicase at telomeres: DNA-PKcs selectively stimulates WRN helicase (but not exonuclease) activity on telomeric D-loop substrates in vitro; in vivo, DNA-PKcs knockdown reduces telomeric G-tail length, which is reversed by WRN helicase overexpression. In vitro helicase/exonuclease assay, siRNA knockdown, G-tail length measurement Aging Medium 20519774
2010 Prkdc participates in mitochondrial genome maintenance: mice with Prkdc mutations show mtDNA depletion in renal tissue upon adriamycin treatment; Prkdc/Mpv17 double-mutant mice develop spontaneous mtDNA depletion, identifying Prkdc as a modifier of mtDNA depletion syndromes even though the protein is not detected in mitochondria. Mouse genetics (Prkdc/Mpv17 double mutants), mtDNA quantification, podocyte overexpression rescue The Journal of clinical investigation Medium 20978358
2012 Upon ionizing radiation, nuclear EGFR associates with DNA-PK and PNPase; DNA-PK phosphorylates PNPase at Ser-776, which impairs its ribonuclease activity toward c-MYC mRNA. A phospho-mimetic S776D PNPase mutant loses ribonuclease activity whereas non-phosphorylatable S776A effectively degrades c-MYC mRNA. Co-immunoprecipitation, in vitro kinase assay, phospho-mimetic/non-phosphorylatable mutants, mRNA stability assay The Journal of biological chemistry Medium 22815474
2013 DNA-PKcs primes ATR/Chk1 activation by phosphorylating RPA32 and TopBP1 in a DNA-structure-specific manner: a gapped linear duplex (juxtaposing a dsDNA end with ssDNA) triggers robust ATR/Chk1 activation in human cell-free extracts in a DNA-PKcs-dependent manner, placing DNA-PKcs upstream of ATR signaling at replication-born DSBs. Human cell-free extract system, defined DNA substrates, immunodepletion, in vitro kinase assay The Journal of cell biology High 23897887
2014 DNA damage triggers DNA-PK-dependent phosphorylation of GOLPH3, which increases GOLPH3 interaction with MYO18A, applying tensile force to the Golgi and causing its dispersal throughout the cytoplasm. Depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage; GOLPH3 overexpression (frequent in cancers) confers resistance. siRNA depletion, co-immunoprecipitation, in vitro kinase assay, confocal microscopy, survival assays Cell High 24485452
2014 DNA-PK phosphorylates FUS at its N-terminus in response to DNA double-strand breaks (calicheamicin treatment), mediating cytoplasmic translocation of FUS, TAF15, EWS, and TRN1 — replicating pathological hallmarks of FTLD-FUS in human cells and neurons. In vitro kinase assay, immunofluorescence, nuclear/cytoplasmic fractionation, phospho-site identification The Journal of neuroscience High 24899704
2014 RNF144A is the first identified mammalian E3 ubiquitin ligase for DNA-PKcs: DNA damage induces p53-dependent RNF144A expression; RNF144A interacts with cytoplasmic DNA-PKcs and ubiquitinates it in vitro and in vivo, promoting its degradation. RNF144A depletion increases DNA-PKcs levels and DNA damage resistance, implicating this pathway in p53-mediated apoptosis. Co-immunoprecipitation, in vitro/in vivo ubiquitination assay, siRNA knockdown, apoptosis assay Proceedings of the National Academy of Sciences of the United States of America High 24979766
2014 DNA-PKcs activates the Chk2-Brca1 pathway during mitosis: DNA-PKcs is required for mitotic Chk2 phosphorylation at Thr68; loss of DNA-PKcs causes chromosome misalignment/lagging due to elevated microtubule dynamics, phenocopying Chk2 and Brca1 deficiency. Phosphomimetic Chk2 or Brca1 rescues the mitotic defects in DNA-PKcs-deficient cells. siRNA knockdown, phospho-specific antibodies, live-cell mitosis imaging, phosphomimetic rescue Oncogenesis Medium 24492479
2014 DNA-PKcs is required to maintain stability of Chk1 and its adaptor Claspin on replication stress: in DNA-PKcs-deficient cells, ATR-dependent Chk1 phosphorylation is compromised, resulting in a defective intra-S checkpoint. DNA-PKcs maintains the Chk1–Claspin complex and transcriptionally regulates Claspin expression. siRNA/genetic knockout, western blotting, ChIP, intra-S checkpoint assay Nucleic acids research Medium 24500207
2015 DNA-PKcs phosphorylates hnRNP-A1 during G2/M phase, promoting the RPA-to-POT1 switch on telomeric 3′ overhangs. In cells lacking DNA-PKcs-dependent hnRNP-A1 phosphorylation, the RPA-to-POT1 switch is impaired, causing DNA damage responses at telomeres during mitosis and induction of fragile telomeres. In vitro kinase assay, phospho-site mutants, co-immunoprecipitation, telomere FISH, DNA damage focus assay Nucleic acids research High 25999341
2016 DNA-PKcs negatively regulates ATM activity through direct phosphorylation of ATM at multiple sites: pre-incubation of ATM with active DNA-PKcs reduces ATM kinase activity in vitro; phospho-mimetic mutations at DNA-PKcs target sites in ATM inhibit ATM signaling, while phospho-blocking mutations increase apoptosis during normal growth, establishing DNA-PKcs as an inhibitory kinase upstream of ATM that controls repair pathway choice. In vitro kinase assay with purified proteins, phospho-mimetic/blocking ATM mutants, chemical inhibitor (DNA-PKcs), genetic deletion in human cells Molecular cell High 27939942
2017 Crystal structure of DNA-PKcs (4.3 Å) in complex with the C-terminal peptide of Ku80 revealed three large structural units (N-terminal unit, Circular Cradle, Head); conformational differences between the two molecules in the asymmetric unit correlate with changes in kinase active-site accessibility, suggesting an allosteric activation mechanism. Ku80ct194 maps near the BRCA1 binding site, suggesting competition that directs pathway choice between NHEJ and HR. X-ray crystallography Science High 28154079
2017 Cryo-EM structure of the DNA-PK holoenzyme (5.8 Å) showed DNA-PKcs, KU70, KU80, and dsDNA form a 650 kDa heterotetramer; the N-terminal solenoid of DNA-PKcs adopts a double-ring fold; DNA-PKcs and KU70/80 form a DNA-binding tunnel protecting ~30 bp DNA. Biochemical analyses showed KU70/80 and DNA coordinately induce conformational changes in DNA-PKcs, allosterically stimulating kinase activity through N-terminal HEAT repeats and FAT domain. Cryo-EM (6.6 Å overall), biochemical kinase assays Cell research High 28840859
2017 Cryo-EM structures of human DNA-PKcs (4.4 Å) and the DNA-PK holoenzyme (5.8 Å) showed the C-terminal globular domain of Ku80 interacts with the arm of DNA-PKcs, and this Ku80-binding site is adjacent to the Ku70/80 DNA-binding region, indicating concerted DNA interaction by both components. Cryo-EM Proceedings of the National Academy of Sciences of the United States of America High 28652322
2019 DNA-PKcs kinase activity drives local chromatin decondensation near DSBs immediately after induction: in cells with kinase-inactive DNA-PKcs, phosphorylation of chromatin factors H2AX and KAP1 is reduced, chromatin fails to decondense near DSBs, and recruitment of many DDR factors is markedly decreased, identifying DNA-PKcs kinase activity as a pioneer initiator of the DDR. Kinase-dead knock-in human cell line, γH2AX and KAP1 phosphorylation, FRET-based chromatin compaction assay, DDR factor recruitment by immunofluorescence Nucleic acids research High 31396623
2020 DNA-PK acts as a sensor of a STING-independent DNA sensing pathway (SIDSP) unique to humans: DNA-PK activity drives a broad antiviral response; heat shock protein HSPA8/HSC70 is a specific phosphorylation target of DNA-PK in this pathway. Viral antagonists HSV-1 ICP0 and adenovirus E1A block this response. DNA damage and foreign DNA trigger distinct modalities of DNA-PK activity. DNA-PK inhibitors, genetic depletion, phosphoproteomics, antiviral assays in human vs. mouse cells Science immunology High 31980485
2020 DNA-PK has a KU-dependent role in 18S rRNA processing and haematopoiesis distinct from NHEJ: KU drives assembly of DNA-PKcs on cellular RNAs including U3 snoRNA; U3 activates purified DNA-PK and triggers DNA-PKcs phosphorylation at T2609. Blocking T2609 (but not S2056) phosphorylation causes KU-dependent defects in 18S rRNA processing, compromised global protein synthesis in haematopoietic cells, and bone marrow failure in mice. DNA-PK resides in nucleoli in an rRNA-dependent manner and co-purifies with the small subunit processome. Mouse knock-in models (kinase-dead; phospho-site mutants), RNA immunoprecipitation, in vitro DNA-PK activation with U3 RNA, ribosome profiling, nucleolar fractionation, co-purification with small subunit processome Nature High 32103174
2020 Cryo-EM structures of DNA-PKcs bound to a DNA end (3.7 Å overall; 3.2 Å for FAT-kinase domain) and of the DNA-PK holoenzyme in both inactive and activated forms revealed the sequential structural transition from inactive to activated states. Kinase activation involves stretching and twisting within individual solenoid segments and loosening of DNA-end binding, uncovering unprecedented structural plasticity of HEAT-repeat proteins as a general regulatory mechanism. Cryo-EM (3.7 Å/3.2 Å resolution) Molecular cell High 33385326
2020 HUWE1 (with UBE2M as E2) mediates poly-neddylation of DNA-PKcs at its kinase domain; inhibition of HUWE1-dependent DNA-PKcs neddylation impairs DNA-PKcs autophosphorylation at Ser2056 and reduces NHEJ efficiency. In vitro neddylation assay, co-immunoprecipitation, siRNA knockdown, NHEJ reporter assay Cell death & disease Medium 32457294
2021 Autophosphorylation of DNA-PKcs at the ABCDE cluster (four Thr residues) causes a gross structural rearrangement that widens the DNA-binding groove, enabling Artemis recruitment and hairpin cleavage. DNA hairpin ends (unlike open DNA ends) specifically promote ABCDE cis-autophosphorylation, while Artemis locks DNA-PK into a kinase-inactive state—revealing a substrate-driven regulatory switch from DNA-end protection to processing. Cryo-EM structures (DNA-PK + DNA before and after phosphorylation; DNA-PK + Artemis + hairpin DNA), in vitro hairpin opening assay Molecular cell High 34936881
2021 DNA-PKcs phosphorylates SOX2 at S251, stabilizing it by preventing WWP2-mediated ubiquitination; this phosphorylation maintains glioma stem cells (GSCs). Upon DNA damage, the DNA-PK complex dissociates from SOX2, which then interacts with WWP2 and is degraded, inducing GSC differentiation. Pharmacological inhibition of DNA-PKcs (NU7441) reduces GSC tumorsphere formation and impairs intracranial GBM xenograft growth. Mass spectrometry (SOX2 interactome), co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, GBM xenografts Science translational medicine High 34193614
2022 DNA-PKcs promotes replication fork reversal independently of its NHEJ role: cells lacking DNA-PKcs activity show reduced fork reversal/slowing in response to replication stress-inducing agents, increased S-phase DNA damage, and sensitivity to replication stress. Inhibiting DNA-PKcs restores chemotherapy sensitivity in BRCA2-deficient mammary tumors with acquired PARPi resistance. DNA fiber assay, electron microscopy of replication forks, DNA-PKcs inhibitors, genetic knockout, BRCA2-deficient tumor models Molecular cell High 36130596
2022 DNA-PKcs interacts with Fis1 and phosphorylates it at Thr34 (TQ motif), increasing Fis1 affinity for Drp1 and inducing mitochondrial fragmentation in tubular cells during acute kidney injury. Knockin mice expressing non-phosphorylatable Fis1-T34A exhibit improved renal function and reduced mitochondrial fragmentation upon AKI. Cytoplasmic DNA-PKcs (normally nuclear) is detected in kidney tissue and patient urinary sediments during septic AKI. Co-immunoprecipitation, in vitro kinase assay, T34A knockin mice, confocal microscopy, renal function assays, patient samples Science signaling High 35290083
2022 The Artemis:DNA-PKcs basal (pre-activated) complex was structurally characterized by cryo-EM: the Artemis catalytic domain is positioned externally to DNA-PKcs prior to ABCDE autophosphorylation; Artemis catalytic and regulatory domains interact with the N-HEAT and FAT domains of DNA-PKcs. A mutually exclusive binding site for Artemis and XRCC4 on DNA-PKcs was defined, and an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. Cryo-EM, native gel electrophoresis, peptide competition assay Nucleic acids research High 35801871
2022 DNA-PK and TRF2 coordinate repression of MRN-initiated resection at blunt (leading-end) telomeres: DNA-PK represses MRN-dependent long-range resection, while TRF2's iDDR inhibits MRN-CtIP endonuclease activity (which would otherwise cleave DNA-PK off blunt ends) both in vitro and in vivo. AlphaFold-Multimer predicts a conserved iDDR–Rad50 interaction interfering with CtIP binding. In vitro resection assay, mouse genetics, AlphaFold-Multimer structural prediction, co-immunoprecipitation Nature structural & molecular biology High 37653239
2023 Cryo-EM visualization of three additional DNA-PKcs transition states during NHEJ showed DNA-PKcs adopts distinct dimeric conformations; upon autophosphorylation, the long-range complex undergoes a substantial conformational change with Ku and DNA-PKcs rotating outward to promote DNA break exposure and DNA-PKcs dissociation. A catalytically inactive dimeric state was also captured, revealing the full regulatory cycle. Single-particle cryo-EM Science advances High 37256947
2022 Physical ARTEMIS:DNA-PKcs interaction is necessary for V(D)J recombination: mutations in DNA-PKcs (L3062R, pathogenic RS-SCID variant) and in Artemis (two conserved regions) that abolish protein-protein interaction impair nuclease function and V(D)J recombination. Minimal interacting fragments were mapped: 42 aa of DNA-PKcs FAT region 2 (residues 3041-3082) mediates interaction with Artemis; 26 aa of Artemis (ARM378-403) constitute the minimal DNA-PKcs-binding fragment. Site-directed mutagenesis, co-immunoprecipitation, V(D)J recombination assay, deletion mapping Nucleic acids research High 35150269
1996 DNA-PKcs (apopain/CPP32 substrate) is cleaved by caspase-3 (apopain) during apoptosis at sites homologous to PARP cleavage; the fragments generated by purified apopain are identical to those in apoptotic cells, establishing DNA-PKcs as a caspase-3 substrate whose cleavage abolishes DNA repair capacity during apoptosis. In vitro caspase cleavage assay with purified apopain, apoptotic cell extracts, inhibitor studies The Journal of experimental medicine High 8642305
2006 A topoisomerase IIβ-mediated dsDNA break at gene promoters recruits DNA-PK (along with PARP-1) as part of a repair/remodeling complex required for regulated transcriptional initiation by nuclear receptors; this identifies DNA-PK as a component of the transcriptional machinery at DNA damage-induced promoter breaks. ChIP, in vitro transcription, PARP-1 activity assay, DSB detection at promoters Science Medium 16794079
2022 DNA-PKcs interacts with and phosphorylates glycolytic enzymes ALDOA and PKM2 in castration-resistant prostate cancer cells; DNA-PK increases enzymatic activity of these glycolytic enzymes, drives synthesis of glucose-derived pyruvate and lactate, and regulates glycolysis in vitro, in vivo, and ex vivo in patient-derived explants. Quantitative proteomics (DNA-PK interactome), in vitro kinase assay, metabolomics, xenografts, patient-derived explants Clinical cancer research Medium 35078861
2020 Hairpinned DNA ends robustly stimulate DNA-PK autophosphorylation specifically at the ABCDE cluster but are ineffective for phosphorylating many other substrates (p53, XRCC4, XLF, HSP90). Phosphorylation of ABCDE sites is requisite for Artemis nuclease activation, revealing a multi-step mechanism of DNA-PK kinase activation dependent on the nature of DNA ends. In vitro kinase assay with defined DNA substrates, phospho-specific antibodies, Artemis nuclease assay Nucleic acids research High 32716029
2018 DNA-PKcs has a kinase-dependent role in suppressing microhomology-mediated end joining during immunoglobulin class switch recombination (CSR): kinase-dead DNA-PKcs severely compromises CSR to IgG1, with frequent interchromosomal translocations, inversions, and extensive end resection; a structural role of DNA-PKcs protein in orienting the DSB ends during CSR is also identified. B cell-specific kinase-dead knock-in mouse model, high-throughput sequencing of CSR junctions Proceedings of the National Academy of Sciences of the United States of America High 30072430
2020 DNA-PKcs T2609 cluster phosphorylation promotes NHEJ pathway choice during CSR: loss of T2609 phosphorylation does not affect CSR efficiency but results in increased chromosomal translocations, end resection, and microhomology usage—hallmarks of alternative end joining—demonstrating that T2609 phosphorylation specifically directs repair toward classical NHEJ. T2609A knock-in mouse model, high-throughput sequencing of CSR junctions Proceedings of the National Academy of Sciences of the United States of America High 32868446

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
1997 DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1783 9363941
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
1998 The complexity of p53 modulation: emerging patterns from divergent signals. Genes & development 1121 9765199
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1993 The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 1074 8422676
1998 DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes & development 1035 9744860
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 996 15758953
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2002 Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 837 11955432
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2006 A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science (New York, N.Y.) 734 16794079
2000 The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes & development 725 10673501
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
1995 DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 689 7671312
1999 Substrate specificities and identification of putative substrates of ATM kinase family members. The Journal of biological chemistry 679 10608806
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
1996 Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death. The Journal of experimental medicine 549 8642305
2010 The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes & development 541 20504901
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2005 mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. The Journal of biological chemistry 527 16221682
2001 DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Current opinion in cell biology 417 11248557
2005 The life and death of DNA-PK. Oncogene 344 15592499
2007 Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. The Journal of cell biology 333 17438073
2019 AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nature communications 276 31699977
2014 DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA repair 271 24680878
2003 ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis 227 12919958
1997 Functional interaction between DNA-PK and c-Abl in response to DNA damage. Nature 224 9109492
2014 Beyond DNA repair: DNA-PK function in cancer. Cancer discovery 208 25168287
2014 DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3. Cell 203 24485452
2010 Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PloS one 183 20617180
2010 A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA repair 174 21030321
2020 ATM, ATR and DNA-PKcs kinases-the lessons from the mouse models: inhibition ≠ deletion. Cell & bioscience 169 32015826
1992 The nuclear serine/threonine protein kinase DNA-PK. Critical reviews in eukaryotic gene expression 162 1486241
2020 Human DNA-PK activates a STING-independent DNA sensing pathway. Science immunology 146 31980485
2017 DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair. Science (New York, N.Y.) 146 28154079
2020 DNA-PKcs: A Multi-Faceted Player in DNA Damage Response. Frontiers in genetics 133 33424929
2000 DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA. Cell 133 11136976
2014 FUS is phosphorylated by DNA-PK and accumulates in the cytoplasm after DNA damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 132 24899704
2004 DNA-PKcs function regulated specifically by protein phosphatase 5. Proceedings of the National Academy of Sciences of the United States of America 119 14734805
1997 DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nature genetics 117 9398856
2024 Quercetin inhibits necroptosis in cardiomyocytes after ischemia-reperfusion via DNA-PKcs-SIRT5-orchestrated mitochondrial quality control. Phytotherapy research : PTR 115 38447978
2016 Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM. Molecular cell 109 27939942
2020 Structure of an activated DNA-PK and its implications for NHEJ. Molecular cell 107 33385326
2002 Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. The EMBO journal 106 12426399
2022 DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction. Journal of advanced research 96 36328752
2010 Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice. The Journal of clinical investigation 95 20978358
2017 Cryo-EM structure of human DNA-PK holoenzyme. Cell research 94 28840859
2022 DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury. Science signaling 93 35290083
2005 DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA. The EMBO journal 89 15678105
2018 Synthetically Lethal Interactions of ATM, ATR, and DNA-PKcs. Trends in cancer 88 30352678
2015 PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. The Journal of allergy and clinical immunology 85 25842288
2023 Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing. Nature communications 84 37580318
2021 Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice. Science translational medicine 78 34193614
2020 DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis. Nature 74 32103174
2019 DNA-PKcs promotes chromatin decondensation to facilitate initiation of the DNA damage response. Nucleic acids research 71 31396623
2014 RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage. Proceedings of the National Academy of Sciences of the United States of America 70 24979766
2017 Cryo-EM structure of the DNA-PK holoenzyme. Proceedings of the National Academy of Sciences of the United States of America 68 28652322
2021 Autophosphorylation transforms DNA-PK from protecting to processing DNA ends. Molecular cell 64 34936881
2020 Targeting DNA-PK in cancer. Mutation research 62 32172133
2014 A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer discovery 61 24556366
2020 Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy. The Journal of clinical investigation 60 31581151
2017 DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 60 28123024
2022 DNA-PKcs: A Targetable Protumorigenic Protein Kinase. Cancer research 58 34893509
2020 Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors. Proceedings of the National Academy of Sciences of the United States of America 58 33020270
2016 Structure-Specific nuclease activities of Artemis and the Artemis: DNA-PKcs complex. Nucleic acids research 57 27198222
2015 DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication. Nucleic acids research 54 25999341
2014 ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers. BBA clinical 54 26674120
2006 The DNA repair complex DNA-PK, a pharmacological target in cancer chemotherapy and radiotherapy. Pathologie-biologie 54 16563661
2020 Uncovering DNA-PKcs ancient phylogeny, unique sequence motifs and insights for human disease. Progress in biophysics and molecular biology 52 33035590
2009 Do DNA repair genes OGG1, XRCC3 and XRCC7 have an impact on susceptibility to bladder cancer in the North Indian population? Mutation research 52 19815090
2018 Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway. Cell death & disease 51 30262880
2010 DNA-PKcs regulates a single-stranded DNA endonuclease activity of Artemis. DNA repair 50 20117966
2020 PRKDC: new biomarker and drug target for checkpoint blockade immunotherapy. Journal for immunotherapy of cancer 47 32238472
2012 Nuclear EGFR suppresses ribonuclease activity of polynucleotide phosphorylase through DNAPK-mediated phosphorylation at serine 776. The Journal of biological chemistry 46 22815474
2013 DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1. Nucleic acids research 44 23775790
2017 A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies. Cancer immunology research 43 28775208
2014 Targeting DNA-PKcs and telomerase in brain tumour cells. Molecular cancer 43 25307264
2022 DNA-PKcs promotes fork reversal and chemoresistance. Molecular cell 42 36130596
2021 Role of PRKDC in cancer initiation, progression, and treatment. Cancer cell international 42 34702253
2014 Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening. BMC cancer 41 25495526
2014 DNA-PKcs activates the Chk2-Brca1 pathway during mitosis to ensure chromosomal stability. Oncogenesis 40 24492479
2011 Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells. Investigational new drugs 40 21221710
2007 DNA-PK phosphorylation sites on Oct-1 promote cell survival following DNA damage. Oncogene 40 17213819
1996 p53 induction, cell cycle checkpoints, and apoptosis in DNAPK-deficient scid mice. Carcinogenesis 40 9006086
2015 DNA-PKcs deficiency inhibits glioblastoma cell-derived angiogenesis after ionizing radiation. Journal of cellular physiology 39 25294801
2014 DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response. Nucleic acids research 39 24500207
2020 CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway. Protein & cell 37 32170574
2020 DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions. Pharmacology & therapeutics 35 32610116
2013 DNA structure-specific priming of ATR activation by DNA-PKcs. The Journal of cell biology 35 23897887
2021 Structural insights into the role of DNA-PK as a master regulator in NHEJ. Genome instability & disease 33 34723130
2005 DNA-PKcs-dependent signaling of DNA damage in Dictyostelium discoideum. Current biology : CB 32 16243037
2021 DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer. Acta pharmaceutica Sinica. B 30 35024317
2020 Discovery and development of novel DNA-PK inhibitors by targeting the unique Ku-DNA interaction. Nucleic acids research 30 33119767
2020 Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors. Molecular oncology 29 32502294
2024 PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT. Cancer research 28 38900943
2010 Coordination of DNA-PK activation and nuclease processing of DNA termini in NHEJ. Antioxidants & redox signaling 28 20698792
2022 Structural analysis of the basal state of the Artemis:DNA-PKcs complex. Nucleic acids research 27 35801871
2019 Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies. Clinical cancer research : an official journal of the American Association for Cancer Research 27 31266833
2018 The role of DNA-PK in aging and energy metabolism. The FEBS journal 27 29453899
2017 Small molecule inhibitors of DNA-PK for tumor sensitization to anticancer therapy. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 27 28820390
2010 Cooperation of DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops. Aging 27 20519774
2023 DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres. Nature structural & molecular biology 26 37653239
2020 HUWE1-dependent DNA-PKcs neddylation modulates its autophosphorylation in DNA damage response. Cell death & disease 26 32457294
2023 Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ. Science advances 25 37256947
2016 Restoration of ATM Expression in DNA-PKcs-Deficient Cells Inhibits Signal End Joining. Journal of immunology (Baltimore, Md. : 1950) 25 26921311
2020 Activation of DNA-PK by hairpinned DNA ends reveals a stepwise mechanism of kinase activation. Nucleic acids research 24 32716029
2018 Kinase-dependent structural role of DNA-PKcs during immunoglobulin class switch recombination. Proceedings of the National Academy of Sciences of the United States of America 24 30072430
2022 A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 23 35078861
2020 DNA-PK, Nuclear mTOR, and the Androgen Pathway in Prostate Cancer. Trends in cancer 23 32209447
2020 DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination. Proceedings of the National Academy of Sciences of the United States of America 23 32868446
2013 PIG3 functions in DNA damage response through regulating DNA-PKcs homeostasis. International journal of biological sciences 22 23678292
2022 DNA-PK Inhibition and Radiation Promote Antitumoral Immunity through RNA Polymerase III in Pancreatic Cancer. Molecular cancer research : MCR 21 35348737
2022 Dynamics of the Artemis and DNA-PKcs Complex in the Repair of Double-Strand Breaks. Journal of molecular biology 21 36270581
2018 Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature. Clinical immunology (Orlando, Fla.) 21 30121298
2024 DNA-PKcs suppresses illegitimate chromosome rearrangements. Nucleic acids research 20 38412274
2022 Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer. Neoplasia (New York, N.Y.) 20 35168148
2020 PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer. eLife 20 32628111
2017 MicroRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC. Cell biology international 20 28328082
2015 DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600. Biochemical and biophysical research communications 20 26381179
2022 Physical ARTEMIS:DNA-PKcs interaction is necessary for V(D)J recombination. Nucleic acids research 19 35150269