DNA-dependent protein kinase catalytic subunit; DNA-PK catalytic subunit; DNA-PKcs; DNPK1; p460 (PRKDC, HYRC, HYRC1)
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Function
- catalytic subunit of dsDNA-associated protein kinase
- serine/threonine protein kinase
- acts as a molecular sensor for DNA damage
- role in DNA nonhomologous end joining (NHEJ) required for double-strand break (DSB) repair & V(D)J recombination
- must be bound to DNA to express its catalytic properties
- promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C)
- assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. required to protect & align broken ends of DNA
- may also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage
- found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability & the prevention of chromosomal end fusion
- also involved in modulation of transcription
- recognizes the substrate consensus sequence [ST]-Q
- phosphorylates Ser-139 of histone variant H2AX/H2AFX, thus regulating DNA damage response
- phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC & RFA2
- can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA
- ability to phosphorylate TP53/p53 in the presence of supercoiled DNA is dependent on C1D
- activity seems to be attenuated by autophosphorylation
- phosphorylated upon DNA damage, probably by ATM or ATR
- autophosphorylated on Thr-2609, Thr-2638 & Thr-2647
- Thr-2609 is a DNA damage-inducible phosphorylation site (inducible with ionizing radiation, IR)
- autophosphorylation induces a conformational change that leads to remodeling of the DNA-PK complex, requisite for efficient end processing & DNA repair
- DNA-PK is a heterotrimer of PRKDC & the Ku p70-p86 (XRCC6-XRCC5) dimer
- formation of this complex may be promoted by interaction with ILF3
- associates with the DNA-bound Ku heterodimer, but it can also bind to & be activated by free DNA
- interacts with DNA-PKcs-interacting protein (KIP) with the region upstream the kinase domain
- PRKDC alone also interacts with & phosphorylates DCLRE1C, thus activating its own latent endonuclease activity
- interacts with C1D
- interacts with TTI1 & TELO2
Structure
- belongs to the PI3/PI4-kinase family
- contains 1 FAT domain
- contains 1 FATC domain
- contains 2 HEAT repeats
- contains 1 PI3K/PI4K domain
- contains 3 TPR repeats
Compartment
Alternative splicing
named isoforms=2
Comparative biology
- SCID mice show deficiencies in p350DNA-PK[2]
- radio-sensitive cell line found to be deficient in p350DNA-PK[3]
- DNA-PK deficient cell lines appear to have normal checkpoint controls (G1->S & G2->M)[4]
Notes
- inhibited by wortmannin
More general terms
Component of
References
- ↑ UniProt http://www.uniprot.org/uniprot/P78527.html
- ↑ 2.0 2.1 NIEHS-SNPs http://egp.gs.washington.edu/data/prkdc/
- ↑ 3.0 3.1 Gottlieb TM, Jackson SP. Protein kinases and DNA damage. Trends Biochem Sci. 1994 Nov;19(11):500-3. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7855895
- ↑ 4.0 4.1 Kirchgessner CU, Patil CK, Evans JW, Cuomo CA, Fried LM, Carter T, Oettinger MA, Brown JM. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science. 1995 Feb 24;267(5201):1178-83. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7855601
- ↑ Lees-Miller SP, Godbout R, Chan DW, Weinfeld M, Day RS 3rd, Barron GM, Allalunis-Turner J. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science. 1995 Feb 24;267(5201):1183-5. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7855602
- ↑ Jackson SP, Jeggo PA. DNA double-strand break repair and V(D)J recombination: involvement of DNA-PK. Trends Biochem Sci. 1995 Oct;20(10):412-5. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8533154