DNA-dependent protein kinase catalytic subunit selections

DNA-dependent protein kinase catalytic subunit; DNA-PK catalytic subunit; DNA-PKcs; DNPK1; p460 (PRKDC, HYRC, HYRC1)

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: nucleus Alternative splicing: named isoforms=2 Notes: - inhibited by wortmannin 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]

General

HEAT repeat-containing protein (HEATR) nuclear protein protein subunit serine/threonine kinase

Properties

SIZE: entity length = 4128 aa MW = 469 kD COMPARTMENT: cell nucleus MOTIF: acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl HEAT repeat {288-323} Ser phosphorylation site {S511} Ser phosphorylation site {S841} Ser phosphorylation site {S893} HEAT repeat {1004-1040} Ser phosphorylation site {S1052} leucine zipper SITE: 1503-1538 FOR-BINDING-VIA: leucine zipper MOTIF: C1D interaction {1503-1538} tetratricopeptide repeat {1723-1756} proteolytic site {2020-2021} Ser phosphorylation site {S2117} binding site SITE: 2436-3212 FOR-BINDING-OF: Ca+2 & integrin-binding protein 1 MOTIF: Thr phosphorylation site {T2603} Thr phosphorylation site {T2609} Ser phosphorylation site {S2612} Thr phosphorylation site {T2638} Thr phosphorylation site {T2647} Thr phosphorylation site {T2649} Thr phosphorylation site {T2671} Ser phosphorylation site {S2672} Tyr phosphorylation site {Y2743} FAT domain NAME: FAT domain SITE: 2883-3539 MOTIF: Tyr phosphorylation site binding site FOR-BINDING-OF: Paxillin tetratricopeptide repeat {2920-2948} tetratricopeptide repeat {2949-2982} Ser phosphorylation site {S3205} PI3K/PI4K {3747-4015} Ser phosphorylation site {S4026} FATC {4096-4128} STATE: active state

References

UniProt :accession P78527
NIEHS-SNPs http://egp.gs.washington.edu/data/prkdc/
Gottlieb TM, Jackson SP. Protein kinases and DNA damage. Trends Biochem Sci. 1994 Nov;19(11):500-3. Review. PMID: 7855895
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: 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: 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: 8533154

Component-of

PRKDC complex

Databases & Figures

OMIM 600899 UniProt P78527 PFAM correlations Entrez Gene 5591 Kegg hsa:5591 ENZYME 2.7.11.1 Figures/diagrams/slides/tables related to DNA-dependent protein kinase catalytic subunit

Contents