DNA-dependent protein kinase catalytic subunit (PRKDC)
The protein contains 4128 amino acids for an estimated molecular weight of 469089 Da.
Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. 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). 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) (PubMed:11955432). 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). Required to protect and align broken ends of DNA (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805). May also 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). Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. 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). Recognize (updated: June 17, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Activation of innate immune response
B cell lineage commitment
Brain development
Cell population proliferation
Cellular protein modification process
Cellular response to DNA damage stimulus
Cellular response to insulin stimulus
DNA repair
Double-strand break repair
Double-strand break repair via alternative nonhomologous end joining
Double-strand break repair via homologous recombination
Double-strand break repair via nonhomologous end joining
Ectopic germ cell programmed cell death
Heart development
Immunoglobulin V(D)J recombination
Innate immune response
Intrinsic apoptotic signaling pathway in response to DNA damage
Maturation of 5.8S rRNA
Negative regulation of apoptotic process
Negative regulation of cellular senescence
Negative regulation of immunoglobulin production
Negative regulation of protein phosphorylation
Negative regulation of response to gamma radiation
Peptidyl-serine phosphorylation
Peptidyl-threonine phosphorylation
Positive regulation of apoptotic process
Positive regulation of developmental growth
Positive regulation of double-strand break repair via nonhomologous end joining
Positive regulation of erythrocyte differentiation
Positive regulation of fibroblast proliferation
Positive regulation of lymphocyte differentiation
Positive regulation of platelet formation
Positive regulation of transcription by RNA polymerase II
Positive regulation of translation
Positive regulation of type I interferon production
Pro-B cell differentiation
Protein destabilization
Protein phosphorylation
Protein ubiquitination
Regulation of circadian rhythm
Regulation of epithelial cell proliferation
Regulation of hematopoietic stem cell differentiation
Regulation of smooth muscle cell proliferation
Response to activity
Response to gamma radiation
Rhythmic process
Signal transduction involved in mitotic G1 DNA damage checkpoint
Small-subunit processome assembly
Somitogenesis
Spleen development
T cell differentiation in thymus
T cell lineage commitment
T cell receptor V(D)J recombination
Telomere capping
Telomere maintenance
Thymus development
Cellular Component
Chromosome, telomeric region
Cytosol
DNA-dependent protein kinase-DNA ligase 4 complex
Extracellular matrix
Membrane
Nonhomologous end joining complex
Nuclear chromosome, telomeric region
Nucleolus
Nucleoplasm
Nucleus
Protein complex
Protein-containing complex
Protein-DNA complex
Small-subunit processome
Transcription regulator complex
Molecular Function
ATP binding
DNA binding
DNA-dependent protein kinase activity
Double-stranded DNA binding
Enzyme binding
Poly(A) RNA binding
Protein domain specific binding
Protein kinase activity
Protein serine kinase activity
Protein serine/threonine kinase activity
Protein threonine kinase activity
RNA binding
Transcription factor binding
U3 snoRNA binding
The reference OMIM entry for this protein is 600899
Protein kinase, dna-activated, catalytic subunit; prkdc
Dna-dependent protein kinase, catalytic subunit; dnpk1
P350
Dna-pkcs
Dna-dependent protein kinase; dnapk
Hyperradiosensitivity complementing 1, mouse, homolog of; hyrc1
DESCRIPTION
The PRKDC gene encodes the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase (DNA-PK), which is involved in DNA nonhomologous end-joining (NHEJ) during DNA double-strand break (DSB) repair and for V(D)J recombination during immune development. The second component of DNA-PK is Ku (XRCC6; 152690), which is required for proper activation of PRKDC (summary by van der Burg et al., 2009 and Woodbine et al., 2013).CLONING
Sipley et al. (1995) reported a partial sequence of the PRKDC gene. Hartley et al. (1995) isolated a PRKDC cDNA, which encodes a 4,096-amino acid protein with a molecular mass of 360 kD. The PRKDC protein showed similarity to phosphatidylinositol 3-kinase family members involved in cell cycle control, DNA repair, and DNA damage responses, and had no detectable activity towards lipids. Other PI kinase proteins involved in DNA repair include FKBP12 (186945) and the ataxia-telangiectasia gene (ATM; 607585), in which mutations lead to genomic instability and predisposition to cancer and ataxia. Independently, Poltoratsky et al. (1995) cloned and sequenced a cDNA encoding the C-terminal 931 amino acids of PRKDC. They showed that this region has homology to phosphatidylinositol kinases.GENE STRUCTURE
Sipley et al. (1995) reported that the PRKDC gene contains 9 exons.MAPPING
By fluorescence in situ hybridization (FISH), Sipley et al. (1995) mapped the PRKDC gene to chromosome 8q11, coincident with XRCC7 (HYRC1), a human homolog of a gene that complements the DNA double-strand break repair and V(D)J recombination defects of hamster V3 and murine severe combined immunodeficient (scid) cells (seeGENE FUNCTION
). Ladenburger et al. (1997) showed that the 5-prime ends of the PRKDC and MCM4 (602638) genes are less than 1 kb apart on 8q12-q13. These genes are transcribed in opposite directions and have autonomous promoters. Satoh et al. (1997) mapped the MCM4 gene to 8q11.2 by FISH. Based on the close proximity of the PRKDC and MCM4 genes, it was assumed that the PRKDC gene also maps to this location. Connelly et al. (1998) reported that the transcription initiation sites of the PRKDC and MCM4 genes are separated by approximately 700 bp, and the start codons by 1,018 bp. The mouse Prkdc gene is located on chromosome 16 (seeANIMAL MODEL
and Bosma et al., 1989, Miller et al., 1993, and Komatsu et al., 1993).GENE FUNCTION
Anderson and Lees-Miller (1992) noted that DNA-PK had been shown in vitro to phosphorylate several transcription factors, suggesting that it functions in cell homeostasis by modulating transcription. DNA-PK activation requires Ku-binding to DNA double-strand breaks or other discontinuities in the DNA double helix, suggesting that DNA-PK recognizes DNA ends at sites of DNA damage or that occur as recombination intermediates. Cells defective in DNA-PK components are hypersensitive to killing by ionizing radiation due to an inability to repair double-strand breaks effectively. Cells defective in either Ku or DNA-PK catalytic subunit are also unable to perform V(D)J recombination, the site-specific recombination process that takes place in developing B and T lymphocytes to generate variable regions of immunoglobulin and T cell receptor genes. In the absence of DNA-PK function, V(D)J recombination intermediates are unable to be processed and ligated (Hartley et al., 1995). Kuhn et al. (1995) and Labhart (1995) ... More on the omim web site
June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
March 3, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 600899 was added.