PRKDC (DNA-PKcs, P78527) curation notes

No deep-research provider was available for this review; these notes were assembled
manually from the UniProt record, the cached publications in publications/, Reactome
entries in reactome/, and a Europe PMC search. Quotes are verbatim from the cached files.

Identity and architecture

• 4128-aa PIKK-family Ser/Thr kinase; HEAT-repeat N-terminal solenoid (double ring),
  FAT, PI3K/PI4K catalytic and FATC domains (UniProt P78527; PANTHER PTHR11139:SF68).
• "DNA-PKcs is a serine/threonine protein kinase comprising a single polypeptide chain of
  4,128 amino acids and belonging to the phosphatidylinositol-3-OH kinase (PI(3)K)-related
  protein family" PMID:20023628.
• Protein kinase, not lipid kinase: "DNA-PK phosphorylates proteins but has no detectable
  activity toward lipids" PMID:7671312.

Core: catalytic subunit of DNA-PK in classical NHEJ and V(D)J recombination

• Holoenzyme: "DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with
  1:1:1:1 stoichiometry" and "KU70/80 and DNA coordinately induce conformational changes of
  DNA-PKcs and allosterically stimulate its kinase activity" PMID:28840859.
• Activated structures 3.2-3.7 A; activation "loosens DNA-end binding" PMID:33385326.
• Long-range synaptic complex with LigIV/XRCC4/XLF; trans-autophosphorylation drives
  transition to short-range complex PMID:33854234; NHEJ supercomplex structures and
  mutational validation PMID:34352203.
• Kinase activity required for DSB rejoining and V(D)J: kinase-dead constructs "fail to
  complement the DNA DSB or V(D)J recombination defects of DNA-PKcs mutant cells"
  PMID:10207111.
• T2609 autophosphorylation required: "Ku-dependent phosphorylation of DNA-PKcs at Thr2609
  is required for the repair of DSBs by NHEJ" PMID:12231622; PP5 dephosphorylates
  PMID:14734805.
• Artemis activation in V(D)J hairpin opening: "Upon complex formation, DNA-PKcs
  phosphorylates Artemis, and Artemis acquires endonucleolytic activity on 5' and 3'
  overhangs, as well as hairpins" PMID:11955432; Reactome R-HSA-5687183.
• Human disease: RS-SCID (IMD26). L3062R patient: mutation "caused insufficient Artemis
  activation" PMID:19075392; compound het patient with SCID plus severe neurological
  phenotype PMID:23722905.
• DNA-PKcs is not essential in human HCT116 cells but its loss gives "profound
  proliferation and genomic stability deficits" PMID:18710952 (abstract only).

Substrates / signalling outputs (non-core, many contexts)

• H2AX S139 (nucleosomal, acetylation-enhanced) PMID:14627815; hypertonic gamma-H2AX
  PMID:16046194.
• LIG4 T650 PMID:15194694; RPA2 S4/S8 (G2/M checkpoint delay) PMID:21731742;
  ASF1A S192 (DNA-PKcs-dependent) PMID:29478807; fumarase T236 (in vitro) PMID:26237645;
  GOLPH3 (Golgi dispersal after damage) PMID:24485452; USF-1 (FAS promoter, insulin)
  PMID:19303849; NR4A3/NOR1 (SMC proliferation) PMID:25852083; PARP1 T594
  PMID:35460603; cGAS (T68/S213) PMID:33273464.
• AKT S473: purified as a membrane-fraction S473 kinase PMID:15262962; DNA-PKcs-SIN1
  (mTORC2) association in UVB-induced S473 phosphorylation PMID:24365180.
  mTORC2 is the predominant S473 kinase in most contexts, so this is context-dependent.

Innate immunity -- conflicting directions

• Positive: "we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that
  activates innate immunity" PMID:23251783; HDP-RNP with HEXIM1/NEAT1 needed for
  cGAS-STING-IRF3 PMID:28712728.
• Negative: "DNA-PK phosphorylates cGAS and suppresses its enzymatic activity"
  PMID:33273464; DNA-PK phosphorylates PARP1 which then PARylates cGAS PMID:35460603.
• Both are curated (activation of innate immune response; negative regulation of
  cGAS/STING). Kept both as non-core; the direction is cell-type/context dependent.

Ribosome biogenesis (non-core, Ku-dependent)

• "DNA-PK has RNA-dependent, cNHEJ-independent functions during ribosome biogenesis that
  require the kinase activity of DNA-PKcs and its phosphorylation at the T2609 cluster";
  U3 snoRNA activates DNA-PK; nucleolar, co-purifies with SSU processome PMID:32103174.
  Northern blots show accumulation of 21S and 12S precursors.
• Nucleolar localization also in PMID:27829214 (immunostaining and fractionation).

Efferocytosis-induced macrophage proliferation (module context)

• PMID:34784501 (mouse macrophages): AC-derived oligonucleotides from DNase II
  activate "a DNA-PKcs-mTORC2/Rictor pathway that increases Myc"; siRNA evidence;
  direct oligonucleotide binding not shown. This is one context of DNA-PKcs as a
  DNA-end/oligonucleotide-activated kinase upstream of AKT; not used to add GO terms here.

Decisions summary

• Core MF: DNA-dependent protein kinase activity (GO:0004677) / protein Ser/Thr kinase.
• Core BP: NHEJ (GO:0006303), immunoglobulin V(D)J recombination (GO:0033152).
• Core CC: DNA-PK complex, NHEJ complex, DNA-PK-Lig4 complex, nucleus.
• Generic protein binding rows removed per policy (Ku, Artemis etc. captured by complex
  and kinase terms).
• G1 checkpoint IMP (PMID:21731742) modified to G2 checkpoint: full text says
  "DNA-PK-dependent RPA2 phosphorylation at S4, S8 appeared to function in the G2/M
  checkpoint".
• Alternative NHEJ (TAS) removed: GO definition requires independence from V(D)J
  recombination factors, of which DNA-PKcs is one.
• Mouse ISS/IEA haematopoiesis-related regulation terms (erythrocyte, platelet, HSC
  differentiation, lymphocyte differentiation, translation) judged over-annotations:
  downstream phenotypes of rRNA-processing or V(D)J defects.
• NEW: site of double-strand break (GO:0035861): phospho-T2609 DNA-PKcs colocalizes with
  gamma-H2AX and 53BP1 foci PMID:12231622.