The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. DNA-PK is thought to act as the “sensor” for DNA double-stranded breaks (DSB), which are considered the most deleterious type of DNA damage. In particular, DNA-PKcs and Ku are shown to be essential for DSB repair through nonhomologous end joining (NHEJ). The phenotypes of animals and human individuals with defective DNA-PKcs or Ku functions indicate their essential roles in these developments, especially in neuronal and immune systems. DNA-PKcs are structurally related to Ataxia–telangiectasia mutated (ATM), which is also implicated in the cellular responses to DSBs. DNA-PKcs and ATM constitute the phosphatidylinositol 3-kinase-like kinases (PIKKs) family with several other molecules.
Cell | Species | Type | Mutation 1 | DNA-PKcs Status | Characteristics | Ref. |
---|---|---|---|---|---|---|
scid | Mouse | Fibroblast | HMZ c.T12138A, p.Y4046X. (4128 aa) |
Protein very low (~1%); DNA binding undetectable; Kinase activity undetectable. |
Increased IR-sensitivity; Reduced DSB repair ability; Defective V(D)J recombination. | [10][11][12][65][66][67] |
V3 | Hamster | Ovary | CHTZ; c.C12070A, p.Q4024X; Not known in the other.(4124 aa) |
Protein undetectable; DNA binding barely detectable; Kinase activity undetectable. |
Increased IR-sensitivity; Defective V(D)J recombination. | [10][68] |
M059J | Human | Glioma | LOH; c.A4051del, p.T1351Pfs*8. (4128 aa) |
Protein undetectable; DNA binding barely detectable; Kinase activity undetectable. |
Increased IR-sensitivity. | [17][69] |
Irs-20 | Hamster | Ovary | CHTZ c.G12358A, p.E4120K; 2nd allele not expressed.(4124 aa) |
Protein reduced (~10% 2); DNA binding reduced (~25% 2); Kinase activity undetectable. |
Increased IR-sensitivity; Defective V(D)J recombination. | [68][70] |
SX-9 | Mouse | Mammary carcinoma | CHTZ c.T9572C, p.L3191P; Not known in the other. (4120 aa) |
Protein reduced (~5% 2); DNA binding reduced (~5% 2); Kinase activity undetectable. |
Increased IR-sensitivity; Defective V(D)J recombination. | [70][71] |
XR-C1 | Hamster | Ovary | Unknown. | Protein undetectable; Kinase activity undetectable. |
Increased IR- and drug (bleomycin and ethyl methane sulfonate) sensitivity; Defective V(D)J recombination. | [72] |
XR-C2 | Hamster | Ovary | c.G12353A, p.G4118E. (4124 aa) |
Protein expression normal; Kinase activity undetectable. |
Increased IR- and drug (bleomycin, ethyl methane sulfonate and mitomycin C)-sensitivity; Reduced DSB repair ability; Defective V(D)J recombination. | [73][74] |
(Generated by gene targeting or genome editing) | ||||||
DT40 | Chicken | B lymphocyte | p. 2888–3012. (4133 aa) |
Protein undetectable. | Normal proliferation; Increased IR-sensitivity. | [75] |
HCT116 | Human | Colon cancer | p. 3831–4127. (4128 aa) |
Protein undetectable; Kinase activity undetectable. |
Reduced proliferation; Increased IR-, drug (etoposide)-sensitivity; Telomere shortening; Increased chromosomal aberrations. | [76] |
TK6 | Human | B lymphocyte | Part of exon 32 replaced with drug resistance gene. | Protein undetectable. | Increased IR-sensitivity. | [77] |
HAP1 | Human | Fibroblast-like, near haploid | 11 bp deletion in exon 25. | Protein undetectable. | Increased drug (Etoposide)-sensitivity. | [78] |
mESC | Mouse | Embryonic stem | c.24del88; p.R9Wfs7*. (4128 aa) |
mRNA very low (<1%). | Upregulation of pluripotency genes. | [79] |
HeLa | Human | Cervical carcinoma |
Targeting exon 36. | Protein undetectable. | Increased IR-sensitivity. | [80] |
Cell | Signal Joint | Coding Joint | Ref. | |||
---|---|---|---|---|---|---|
Frequency | Structure | Frequency | Structure | |||
Mouse scid (SCGR11) | Normal. | Fidelity slightly decreased (~80%). | Significant decrease (~3%). | Larger deletions. | [81] | |
V3 | Mild decrease (~20%). | Fidelity modestly decreased (~50%). | Significant decrease (~1%). | Abnormally large P elements. | [10] | |
Mouse scid (SCID/St) | Substantial decrease (~10%). | Not described. | Significant decrease (~0.1%). | Not described. | [11] | |
IRS-20 | Substantial decrease (~10%). | Fidelity slightly decreased (~75%). | Significant decrease (~3%). | Smaller deletions than scid and V3. | [68] | |
SX-9 | Substantial decrease (~10%). | Fidelity profoundly decreased (~10%). | Significant decrease (~3%). | Slightly longer deletions. | [71] | |
XR-C1 | Significant decrease (~2%). | Correct joins absent (0%). | Significant decrease (~2%). | Not described. | [72] | |
XR-C2 | Mild decrease (~30%). | Not described. | Mild decrease (~50%). | Not described. | [73] | |
xrs6 ( Ku80) |
Significant decrease (~5%). | Fidelity profoundly decreased (~15%). | Significant decrease (~1%). | None recovered. | [81] | |
XR-V15B (-Ku80) |
Undetectable (<1%). | Not described. | Undetectable (<1%). | Not described. | [19] | |
XR-1 (-XRCC4) |
Significant decrease (~2%). | Fidelity profoundly decreased (~20%). | Significant decrease (~0.2%). | Larger deletions. |
|
Animal | Mutation | DNA-PKcs Status | Animal Phenotype | Cellular Phenotype 1 | Ref. |
---|---|---|---|---|---|
Mouse scid | c.T12138A, p.Y4046X. (4128 aa) |
Protein very low (~1%); DNA binding undetectable; Kinase activity undetectable. |
SCID; Increased thymic lymphomas. | Increased IR-sensitivity; Reduced DSB repair ability; Defective V(D)J recombination (CJ but not SJ). | [10,11,12,66,67,68] |
Mouse, gene knockout | Insertion of drug resistance gene in exon 6. | mRNA undetectable; Protein undetectable; Kinase activity undetectable. |
SCID. | Increased IR-sensitivity. | [82] |
Mouse, gene knockout | p. 3860–3950. (4128 aa) |
Protein undetectable; Kinase activity undetectable. |
SCID. | Defective V(D)J recombination (CJ but not SJ); Increased IR-sensitivity (fibroblast); Normal IR-sensitivity (ES). | [83] |
Mouse, gene knockout | 3′-half of exon 3 replaced with drug resistance gene. | Protein undetectable. | SCID. | Increased IR-sensitivity. | [84] |
Mouse slip | A transgene inserted by > 20 copies to upstream of three exons corresponding to 777–1010 nucleotides of mRNA. | mRNA undetectable; Kinase activity undetectable. |
SCID; Increased thymic lymphomas. | Not described. | [85][86] |
Mouse, KD | c.A11765C, p.D3922A. (4128 aa) |
Protein expression normal; Kinase activity undetectable. |
Embryonic lethal (E14.5); Defective neuronal development. | Increased IR-sensitivity; Increased genomic instability; Defective V(D)J recombination (CJ and SJ). | [87] |
Mouse, 3A |
c.A7813/7900 /7927G p.T2605/2634/2643A. (4128 aa) |
Protein expression normal; Kinase activity normal. |
Born at normal ratio and size, but becomes smaller 2–3 weeks of age; Death shortly after birth (75% within 4 w); Congenital bone marrow failure; Loss of hematopoietic stem cells. | Increased sensitivity to IR, UV, CPT and MMC. | [88] |
Mouse, Balb/c, C.B.17, 129 |
c.C6418T, p.R2140C/c.A11530G, p.M3844V. | Protein expression decreased (5–10%); Kinase activity reduced (5–10%). |
Immunologically normal; Normal development; Increased thymocyte apoptosis; Susceptible to cancer, including breast cancer and thymic lymphoma. | Delay in DSB repair; Increased chromosome instability. | [89][90][91] |
Horse SCID (Arabian foal) |
c.9478del5, p.S3160Nfs4*. (4134 aa) |
Protein undetectable; Kinase activity undetectable. |
SCID. | Increased IR-sensitivity; Defective V(D)J recombination (CJ and SJ). | [92][93][94] |
Dog SCID (Jack Russel Terriers) |
c.G10879A, p.E3627X. (4144 aa) |
Protein undetectable; DNA binding barely detectable; Kinase activity undetectable. |
SCID. | Increased IR-sensitivity; Defective V(D)J recombination (CJ and SJ). | [95][96] |
Rat, gene knockout | Deletion in exon 1, causing frame-shift. (4126 aa) |
mRNA undetectable; Protein undetectable. |
SCID; Defective lymphocyte development; Growth retardation; Reduced litter size (~1/2). |
Reduced proliferation; Premature senescence; IR-sensitivity; Defective NHEJ. | [97] |
Zebrafish, gene knockout | Frame-shift in exon 3. (4119 aa) |
Protein undetectable. | SCID; Growth delay up to 3 months. |
Not described. | [98] |
Zebrafish, gene knockout | c.10835del8, p.D3612Vfs17. (4119 aa) |
Not described. | SCID; IR-sensitivity. |
Not described. | [99] |
Mice | Viability | Growth | Neurogenesis | Immunity 1 | Ref. |
---|---|---|---|---|---|
DNA-PKcs−/− | Viable. | Normal body size. | Normal. | SCID (leaky); SJ: normal or modestly impaired; CJ: impaired. | [84,85,86,106] |
Ku80−/− | Viable. | Reduced body size. | Defective (milder than XRCC4−/− and LIG4−/−); Increased cell death. | SCID; SJ & CJ: defective. | [101,102,106] |
Ku70−/− | Viable. | Reduced body size. | Defective (milder than XRCC4−/− and LIG4−/−); Increased cell death. | SCID (leaky); SJ & CJ: defective. | [103,104,106] |
LIG4−/− | Late embryonic lethality (>E13.5) | Reduced body size in uterus. | Severely defective; Massive cell death. | SCID; SJ & CJ: defective. | [107][108] |
XRCC4−/− | Late embryonic lethality (>E13.5) | Reduced body size in uterus. | Severely defective; Massive cell death. | SCID; SJ & CJ: defective. | [109] |
Artemis−/− | Viable. | Normal body size. | Normal. | SCID (leaky); SJ: normal; CJ: impaired. | [110] |
XLF−/− | Viable. | Normal body size. | Normal. | Mostly normal; Slight decrease in the number of lymphocytes; Normal lymphocyte distribution; Mild defect in CSR. | [111] |
PAXX−/− | Viable. | Normal body size. | Normal. | Mostly normal; Modest decrease in the number of lymphocytes. | [112][113] |
Patient | Gender | Ethnic Origin | Mutation 1 and DNA-PK Status | Clinical Characteristics | Cellular Characteristics | Ref. |
---|---|---|---|---|---|---|
P1 (ID177) |
F | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. Protein expression normal; Kinase activity normal. |
SCID. | Increased IR-sensitivity; Delay in DSB repair. | [116] |
P2 (NM720) |
M | British | CHTZ; c. exon16; c.C10721T, p.A3574V. Protein very low (~5% 2); Kinase activity undetectable. |
SCID; Growth failure; Microcephaly; Facial dysmorphism; Seizures; Bilateral sensorineural hearing loss; Visual impairment; Died at 31 months. | Increased IR-sensitivity; Delay in DSB repair. | [119] |
P3 | M | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. |
SCID; Granuloma; Autoimmunity. | Not described. | [117] |
P4 | F | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. |
SCID; Granuloma; Autoimmunity. | Not described. | [117] |
P5 | F | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. |
SCID; Granuloma; Arthritis. | Not described. | [118] |
P6 | F | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. |
SCID; Granuloma; Diarrhea. | Not described. | [118] |
This entry is adapted from the peer-reviewed paper 10.3390/genes12081143