Alternative titles; symbols
HGNC Approved Gene Symbol: PRKDC
Cytogenetic location: 8q11.21 Genomic coordinates (GRCh38): 8:47,773,111-47,960,136 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q11.21 | Immunodeficiency 26, with or without neurologic abnormalities | 615966 | Autosomal recessive | 3 |
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).
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.
Sipley et al. (1995) reported that the PRKDC gene contains 9 exons.
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 (see GENE 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 (Bosma et al., 1989, Miller et al., 1993, and Komatsu et al., 1993).
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) reported that DNA-PK suppressed RNA polymerase I transcription in both mouse and purified Xenopus cell extract, respectively, but did not inhibit transcription by RNA polymerases II or III (Labhart, 1995).
Lees-Miller et al. (1995) showed that the radiosensitive human malignant glioma M059J cell line is defective in DNA double-strand break repair and fails to express the p350 subunit of DNA-PK.
Shieh et al. (1997) demonstrated that p53 (191170) was phosphorylated at ser15 and ser37 by purified DNA-PK, and that this modification impaired the ability of MDM2 (164785) to inhibit p53-dependent transactivation. They presented evidence that these effects were most likely due to a conformational change induced by phosphorylation of p53.
Daniel et al. (1999) demonstrated that the PRKDC protein participates in retroviral DNA integration, which is catalyzed by the viral protein integrase. Prkdc-deficient murine scid cells infected with 3 different retroviruses showed a substantial reduction in retroviral DNA integration and died by apoptosis. Scid cell killing was not observed after infection with an integrase-defective virus, suggesting that abortive integration is the trigger for death in these DNA repair-deficient cells. These results suggested that the initial events in retroviral integration are detected as DNA damage by the host cell, and that completion of the integration process requires the DNA-PK-mediated repair pathway.
Jimenez et al. (1999) demonstrated that the p53 response was fully functional in primary mouse embryonic fibroblasts lacking Prkdc: irradiation-induced DNA damage in these defective fibroblasts induced a normal response of p53 accumulation, phosphorylation of p53 serine residue at position 15, nuclear localization, and binding to DNA of p53. Jimenez et al. (1999) also reported that the Prkdc-deficient cell line contained a homozygous mutation in the DNA-binding domain of p53, which may explain the defective response by p53 reported in this line by Woo et al. (1998). Jimenez et al. (1999) concluded that DNA-PK activity was not required for cells to mount a p53-dependent response to DNA damage.
In mammalian cells, abrogation of telomeric repeat-binding factor TRF2 (TERF2; 602027) or DNA-PK activity causes end-to-end chromosomal fusion, establishing a central role for these proteins in telomere function. Bailey et al. (2001) demonstrated that TRF2-mediated end-capping occurred after telomere replication. The postreplicative requirement for TRF2 and DNA-PK catalytic subunit was confined to only the half of the telomeres that were produced by leading-strand DNA synthesis. Bailey et al. (2001) concluded that there was a crucial difference in postreplicative processing of telomeres that was linked to their mode of replication.
Ma et al. (2002) determined that the Artemis protein (DCLRE1C; 605988) formed a complex with PRKDC in the absence of DNA. The purified Artemis protein alone possessed single-strand-specific 5-prime-to-3-prime exonuclease activity. Upon complex formation, PRKDC phosphorylated Artemis, and Artemis acquired endonucleolytic activity on 5-prime and 3-prime overhangs, as well as hairpins. The Artemis-PRKDC complex can open hairpins generated by the RAG (see 179615) complex. Ma et al. (2002) concluded that PRKDC regulates Artemis by both phosphorylation and complex formation to permit enzymatic activities that are critical for the hairpin-opening step of V(D)J recombination and for the 5-prime and 3-prime overhang processing in nonhomologous DNA end joining.
Falck et al. (2005) identified related, conserved C-terminal motifs in human NBS1 (602667), ATRIP (606605), and Ku80 (194364) proteins that are required for their interaction with members of the phosphoinositide 3-kinase-related protein kinase (PIKK; see 607032) family, ATM (607585), ATR (601215), and DNA-PKcs, respectively. These EEXXXDDL motifs are essential not only for efficient recruitment of ATM, ATR, and DNA-PKcs to sites of damage, but are also critical for ATM-, ATR-, and DNA-PKcs-mediated signaling events that trigger cell cycle checkpoints and DNA repair. Falck et al. (2005) concluded that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signaling.
Soutoglou and Misteli (2008) demonstrated that prolonged binding of DNA repair factors to chromatin can elicit the DNA damage response in an ATM- and DNAPK-dependent manner in the absence of DNA damage. Targeting of single repair factors to chromatin revealed a hierarchy of protein interactions within the repair complex and suggested amplification of the damage signal. Soutoglou and Misteli (2008) concluded that activation of the DNA damage response does not require DNA damage, and stable association of repair factors with chromatin is likely a critical step in triggering, amplifying, and maintaining the DNA damage repair signal.
Lu et al. (2008) reported that the kinase activity of the Artemis:PRKDC complex could be activated by hairpin DNA ends in cis, allowing nicking of hairpins, followed by processing and joining by nonhomologous DNA end joining. These insights enabled reconstitution of many aspects of antigen receptor diversification of V(D)J recombination using 13 highly purified polypeptides, thereby permitting variable domain exon assembly. The features of the recombination sites created by this biochemical system included all of the features observed in vivo, such as nucleolytic resection, P nucleotides, and N nucleotide addition, and indicated that most, if not all, of the end modification enzymes had been identified.
Burleigh et al. (2020) found that the E1A oncogene of human adenovirus-5 blocked distinct STING (STING1; 612374)-dependent and -independent DNA-sensing pathways in human cells. Activation of the STING-independent DNA-sensing pathway (SIDSP) in human cells required exposed DNA ends and relied on DNAPK and its cofactors, Ku70 and Ku80, to sense those ends. The DNAPK-dependent SIDSP was present in humans, primates, and rats, but it was absent or severely impaired in mouse. In humans, the DNAPK-dependent SIDSP activated a potent, broad gene expression program for DNA-activated antiviral response. DNAPK targeted HSPA8 (600816) and phosphorylated it at ser638 in the antiviral SIDSP response. The ICP0 ubiquitin ligase of herpes simplex virus-1 inhibited the antiviral SIDSP by blocking DNA-activated HSPA8 phosphorylation. DNAPK-dependent SIDSP was triggered only by foreign DNA in human cells and not by DNA damage.
In a Turkish girl with immunodeficiency-26 (IMD26; 615966) manifest as severe combined immunodeficiency (SCID) with lack of T or B cells and increased cellular sensitivity to radiation, van der Burg et al. (2009) identified a homozygous missense mutation in the PRKDC gene (L3062R; 600899.0001).
In a boy with IMD26 and profound neurologic abnormalities, Woodbine et al. (2013) identified compound heterozygous mutations in the PRKDC gene (A3574V, 600899.0002 and Ex16del, 600899.0003). Functional studies were consistent with a loss of function, resulting in decreased protein expression, loss of kinase activity, and impaired NHEJ and DSB repair. Noting that animal models of Prkdc loss do not show neurologic abnormalities, Woodbine et al. (2013) postulated that DSB repair plays a role in nonhomologous recombination during neuronal development and maintenance in humans.
Bosma et al. (1983) reported homozygous mice with features of severe combined immunodeficiency (scid), including lymphopenia, hypogammaglobulinemia, and impaired immune functions mediated by T and B lymphocytes. Hendrickson et al. (1988) determined that the defect in the scid mouse resides in the gene for a transacting factor that mediates the rejoining event for rearrangement of the immunoglobulin gene; heavy-chain gene rearrangement was found to be blocked at the D-J stage.
By linkage of scid to mahoganoid (md), a recessive mouse coat color marker on chromosome 16, Bosma et al. (1989) determined that autosomal recessive murine scid maps to the centromeric end of chromosome 16. Miller et al. (1993) constructed a refined linkage map of the centromeric region of mouse chromosome 16, placing the scid gene between Prm2 (182890) and Igl1. No recombination was found between scid and the VpreB and lambda-5 genes which are specific to developmental stages of B cells.
Komatsu et al. (1993) introduced fragments of human chromosome 8 into cells derived from scid mice by X-irradiation and somatic cell fusion. The resulting hybrid clones contained human DNA fragments that complemented the hyperradiosensitivity of the scid cells. Alu-PCR products from these hybrids were used for chromosome painting by the technique of chromosome in situ suppression hybridization, allowing assignment of the human homolog of the mouse scid locus, HYRC1 (hyperradiosensitivity complementing-1), to human chromosome 8q11. Using the same microcell technique, Kurimasa et al. (1994) demonstrated correction of radiation sensitivity by a fragment of human chromosome 8 representing 8p11.1-q11.1. Using similar methods, Komatsu et al. (1995) demonstrated that the scid cells were also fully complemented for the V(D)J recombination reaction, whereas the uncomplemented control cells failed to carry out V(D)J recombination normally. The findings indicated that the HYRC1 locus encodes the SCID factor involved in all V(D)J recombination coding joint formation and in 30 to 35% of repair of double-strand breaks.
Kirchgessner et al. (1995) identified PRKDC as a strong candidate for the human homolog of the mouse scid gene. Chromosomal fragments expressing PRKDC complemented the scid phenotype, and PRKDC protein levels were greatly reduced in cells derived from scid mice compared to cells from wildtype mice. The authors established the existence of a new synteny group between human chromosome 8q11, containing the p350 gene and the CEBPD gene (116898), and the centromeric region of mouse chromosome 16 at the position of the scid locus.
Miller et al. (1995) used a partial cDNA clone for human PRKDC to map the mouse homolog using a large interspecific backcross panel. They found that the mouse gene did not recombine with scid, consistent with the hypothesis that scid results from a mutation in the mouse Prkdc gene.
In 4 individual scid mice, Araki et al. (1997) demonstrated a T-to-A transversion in codon tyr4406 of the Prkdc gene, resulting in a nonsense mutation and a truncated protein missing 83 amino acids. The mutation was in the phosphatidylinositol 3-kinase domain of the protein. The same mutation was found in the scid mouse by Blunt et al. (1996) and Danska et al. (1996).
Hendrickson (1993) reviewed the relevance of the scid mouse as an animal model system for studying human disease.
SCID in Arabian foals is an autosomal recessive mutation that results in primary immunodeficiency. Wiler et al. (1995) showed that SCID in Arabian horses is almost precisely analogous to that found in mice. The horses had severely depressed numbers of both B and T lymphocytes, whereas natural killer cell activity was normal. In studies of the equine disorder, Wiler et al. (1995) showed that the factor defective is required for V(D)J recombination, resistance to ionizing radiation, and DNA-dependent protein kinase activity. The authors concluded that the Prkdc gene is defective in both mice and Arabian foals with scid.
In a Turkish girl, born of consanguineous parents, with immunodeficiency-26 (IMD26; 615966) manifest as infantile-onset severe combined immunodeficiency (SCID) with absent B and T cells, van der Burg et al. (2009) identified a homozygous c.9185T-G transversion in the PRKDC gene, resulting in a leu3062-to-arg (L3062R) substitution at a highly conserved residue in the FAT domain. The unaffected parents were heterozygous for the mutation. The patient also carried a homozygous deletion of Gly2113, but this residue is not well conserved and was demonstrated to be nonpathogenic. Studies of patient cells showed normal DNA-PK kinase and autophosphorylation capacity. Patient bone marrow cells showed increased long palindromic (P)-nucleotide stretches in the immunoglobulin coding joints, indicating a defect in hairpin opening and insufficient Artemis (605988) activation. PRKDC-deficient cells showed abnormal junctional pattern during V(D)J recombination, as well as impaired nonhomologous end-joining that could not be restored to normal by mutant L3062R. Van der Burg et al. (2009) noted that the L3062R mutation, which retains kinase and autophosphorylation activity, differs substantially from the spontaneous Prkdc mutations described in SCID horses, mice, and dogs, all of which result in truncated proteins.
In a boy with immunodeficiency-26 (IMD26; 615966) with neurologic abnormalities, Woodbine et al. (2013) identified compound heterozygous mutations in the PRKDC gene: a c.10721C-T transition, resulting in an ala3574-to-val (A3574V) substitution inherited from the unaffected mother on 1 allele, and a cDNA that lacked exon 16 on the other allele (Ex16del; 600899.0003). Genomic sequencing of the patient's DNA showed a 1-bp insertion (IVS16+1510insA) 700 bp upstream of the intron 16 splice site on the other allele, but it was unclear whether or not this change caused the in-frame skipping of exon 16. Immortalized patient cells showed decreased but detectable PRKDC protein, but no detectable kinase activity; the mother's cells had about 50% residual PRKDC kinase activity. Patient cells showed a defect in DNA double-strand break repair following irradiation, which could be rescued by expression of wildtype PRKDC. The A3574V substitution occurred at a highly conserved residue within the FAT domain, which lies outside the kinase domain. Cells transfected with the mutation showed impaired PRKDC function in response to irradiation and a less severe defect in V(D)J end-joining, suggesting that the missense mutation retained some functional capacity. Functional studies of cells lacking exon 16 suggested that it represented a null allele. The overall findings were consistent with a loss of function. In addition to SCID, the patient had microcephaly, brain malformations, hearing loss, visual impairment, and little developmental progress; he died at age 31 months with intractable seizures.
For discussion of the Ex16del mutation in the PRKDC gene that was found in compound heterozygous state in a patient with immunodeficiency-26 (IMD26; 615966) with neurologic abnormalities by Woodbine et al. (2013), see 600899.0002.
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