Phospho-PRKDC (Ser2056)

Phospho-PRKDC (Ser2056)

Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage (PubMed:11955432, PubMed:12649176, PubMed:14734805, PubMed:33854234).
Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination (PubMed:11955432, PubMed:12649176, PubMed:14734805, PubMed:33854234).
Must be bound to DNA to express its catalytic properties (PubMed:11955432).
Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C) (PubMed:11955432).
Recruited by XRCC5 and XRCC6 to DNA ends and is required to 1 protect and align broken ends of DNA, thereby preventing their degradation, 2 and sequester the DSB for repair by NHEJ (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805, PubMed:33854234).
Act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805).
The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805).
Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion (By similarity).
Also involved in modulation of transcription (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805).
As part of the DNA-PK complex, involved in the early steps of ribosome assembly by promoting the processing of precursor rRNA into mature 18S rRNA in the small-subunit processome (PubMed:32103174).
Binding to U3 small nucleolar RNA, recruits PRKDC and XRCC5/Ku86 to the small-subunit processome (PubMed:32103174).
Recognizes the substrate consensus sequence [ST]-Q (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805).
Phosphorylates 'Ser-139' of histone variant H2AX, thereby regulating DNA damage response mechanism (PubMed:14627815, PubMed:16046194).
Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, FH, SRF, NHEJ1/XLF, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2 (PubMed:2507541, PubMed:2247066, PubMed:1597196, PubMed:8407951, PubMed:8464713, PubMed:9362500, PubMed:9139719, PubMed:10026262, PubMed:10467406, PubMed:12509254, PubMed:11889123, PubMed:14612514, PubMed:14599745, PubMed:15177042, PubMed:18644470, PubMed:26666690, PubMed:30247612, PubMed:14704337, PubMed:16397295, PubMed:26237645, PubMed:28712728).
Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA (PubMed:9679063).
Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D (PubMed:9363941).
Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect mechanism (By similarity).
Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728).
Also regulates the cGAS-STING pathway by catalyzing phosphorylation of CGAS, thereby impairing CGAS oligomerization and activation (PubMed:33273464).

Activation of innate immune responseManual Assertion Based On ExperimentIDA:UniProtKB
B cell lineage commitmentIEA:Ensembl
Brain developmentIEA:Ensembl
Cellular protein modification processManual Assertion Based On ExperimentTAS:ProtInc
Cellular response to DNA damage stimulusManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to insulin stimulusManual Assertion Based On ExperimentIMP:BHF-UCL
Double-strand break repairManual Assertion Based On ExperimentIMP:BHF-UCL
Double-strand break repair via alternative nonhomologous end joiningManual Assertion Based On ExperimentTAS:BHF-UCL
Double-strand break repair via nonhomologous end joiningTAS:Reactome
Ectopic germ cell programmed cell deathIEA:Ensembl
Heart developmentIEA:Ensembl
Immunoglobulin V(D)J recombinationManual Assertion Based On ExperimentIBA:GO_Central
Innate immune responseIEA:UniProtKB-KW
Intrinsic apoptotic signaling pathway in response to DNA damageManual Assertion Based On ExperimentIBA:GO_Central
Maturation of 5.8S rRNAManual Assertion Based On ExperimentIDA:UniProtKB
Mitotic G1 DNA damage checkpoint signalingManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of apoptotic processManual Assertion Based On ExperimentIMP:CACAO
Negative regulation of protein phosphorylationISS:UniProtKB
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Peptidyl-threonine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of apoptotic processIEA:Ensembl
Positive regulation of double-strand break repair via nonhomologous end joiningManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of erythrocyte differentiationISS:UniProtKB
Positive regulation of lymphocyte differentiationISS:UniProtKB
Positive regulation of platelet formationISS:UniProtKB
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of translationISS:UniProtKB
Pro-B cell differentiationIEA:Ensembl
Protein destabilizationIEA:Ensembl
Protein phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of circadian rhythmISS:UniProtKB
Regulation of epithelial cell proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Regulation of hematopoietic stem cell differentiationISS:UniProtKB
Regulation of smooth muscle cell proliferationManual Assertion Based On ExperimentIMP:UniProtKB
Response to gamma radiationIEA:Ensembl
Rhythmic processIEA:UniProtKB-KW
Small-subunit processome assemblyManual Assertion Based On ExperimentIDA:UniProtKB
SomitogenesisIEA:Ensembl
T cell differentiation in thymusIEA:Ensembl
T cell lineage commitmentIEA:Ensembl
T cell receptor V(D)J recombinationIEA:Ensembl
Telomere cappingManual Assertion Based On ExperimentIMP:BHF-UCL
Telomere maintenanceManual Assertion Based On ExperimentIBA:GO_Central

Nucleus
Nucleus, nucleolus

Immunodeficiency 26 with or without neurologic abnormalities (IMD26):
A form of severe combined immunodeficiency characterized by reduced or absent T and B cells, recurrent candidiasis, and lower respiratory tract infections. Some patients show dysmorphic features, severe growth failure, microcephaly, seizures, and impaired neurological functions.

Autophosphorylated at two clusters, the T2609 cluster and the S2056 cluster (PubMed:33854234).
Autophosphorylated on Ser-2056, Thr-2609, Thr-2638 and Thr-2647 (PubMed:14734805, PubMed:12186630, PubMed:12231622, PubMed:33854234).
Ser-2056 and Thr-2609 are DNA damage-inducible phosphorylation sites (inducible with ionizing radiation, IR) dephosphorylated by PPP5C (PubMed:14734805, PubMed:12186630, PubMed:12231622).
Autophosphorylation induces a conformational change that leads to remodeling of the DNA-PK complex, requisite for efficient end processing and DNA repair (PubMed:14734805, PubMed:12186630, PubMed:12231622).
Autophosphorylation in trans within DNA-PK complexes loaded on DNA ends leads to the dissociation of PRKDC from DNA and the transition into the short-range NHEJ complex (PubMed:33854234).
Autophosphorylation of the T2609 cluster is required for hematopoietic development and protein synthesis in erythrocytes precursors (By similarity).
S-nitrosylated by GAPDH.
Polyubiquitinated by RNF144A, leading to proteasomal degradation.