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.
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Cell | Species | Type | Mutation | 1 | DNA-PKcs Status | Characteristics | Ref. |
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Frequency | |
---|---|
Structure |
scid | Mouse |
Mouse | scid | |||
Fibroblast | ||||
(SCGR11) | Normal. | Fidelity slightly decreased (~80%). | Significant decrease (~3%). | Larger deletions. |
Mouse | scid | c.T12138A, p.Y4046X. (4128 aa) | HMZ c.T12138A, p.Y4046X. (4128 aa) |
Protein very low (~1%); DNA binding undetectable; | ||||||||||||||
[ | 81 | ] | ||||||||||||||||
Kinase activity undetectable. | SCID; Increased thymic lymphomas. | Protein very low (~1%); DNA binding undetectable; | Kinase activity undetectable. |
Increased IR-sensitivity; Reduced DSB repair ability; Defective V(D)J recombination. | Increased IR-sensitivity; Reduced DSB repair ability; Defective V(D)J recombination (CJ but not SJ). | [ | 10 | , | 11 | , | 12 | , | 66 | , | 67 | [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] | |||||||||
, | 68 | ] | ||||||||||||||||
V3 | Mild decrease (~20%). | Fidelity modestly decreased (~50%). | Significant decrease (~1%). | Abnormally large P elements. | ||||||||||||||
Mouse, gene knockout | Insertion of drug resistance gene in exon 6. | mRNA undetectable; Protein undetectable; Kinase activity undetectable. | ||||||||||||||||
[ | 10 | ] | ||||||||||||||||
SCID. | Increased IR-sensitivity. | [ |
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 | ] | |||||||
82 | |||||||||||||||||||||
Ku80 | −/− | Viable. | Reduced body size. | ] | Defective (milder than XRCC4 | −/− | and LIG4 | −/− | ); Increased cell death. | SCID; SJ & CJ: defective. | [ | 101 | , | 102 | , | 106 | ] | M059J | |||
Mouse | |||||||||||||||||||||
Human | |||||||||||||||||||||
scid | |||||||||||||||||||||
Glioma | |||||||||||||||||||||
(SCID/St) | |||||||||||||||||||||
LOH; | |||||||||||||||||||||
Substantial decrease (~10%). | |||||||||||||||||||||
c.A4051del, p.T1351Pfs*8. | |||||||||||||||||||||
Not described. | Significant decrease (~0.1%). | Not described. | [ | ||||||||||||||||||
Ku70 | −/− | ||||||||||||||||||||
11 | |||||||||||||||||||||
Mouse, gene knockout | |||||||||||||||||||||
] | |||||||||||||||||||||
p. 3860–3950. | (4128 aa) |
Protein undetectable; |
Viable.Kinase activity undetectable. | (4128 aa) | Protein undetectable; DNA binding barely detectable; Kinase activity undetectable. |
SCID. | Increased IR-sensitivity. | Reduced body size. | Defective (milder than XRCC4 | −/− | and LIG4 | −/− | ); Increased cell death.Defective V(D)J recombination (CJ but not SJ); Increased IR-sensitivity (fibroblast); Normal IR-sensitivity (ES). | SCID (leaky); SJ & CJ: defective. | [ | 103 | , | 104 | , | 106 | ] |
LIG4 | −/− |
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. | 83 | ] | 17 | ] | [69] | ||||||
SCID; Granuloma; Autoimmunity. | Not described. | [ | 117 | ] | Irs-20 | Hamster | Ovary | |||||||
IRS-20 | Substantial decrease (~10%). | Fidelity slightly decreased (~75%). | ||||||||||||
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 | ] | [ | ||
Significant decrease (~3%). | ||||||||||||||
70 | ] | |||||||||||||
Smaller deletions than | scid | and V3. | [ | 68 | ] | |||||||||
Mouse, gene knockout | 3′-half of exon 3 replaced with drug resistance gene. | Protein undetectable. | SCID. | Increased IR-sensitivity. | [ | Late embryonic lethality (>E13.5) | Reduced body size in uterus. | Severely defective; Massive cell death. | 84] | SCID; SJ & CJ: defective. | [ | |||
P4 | F | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. | 107 | ] | SCID; Granuloma; Autoimmunity. | [108] | |||||||
Not described. | [ | 117 | ] | SX-9 | XRCC4Mouse | 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. |
SX-9 | Substantial decrease (~10%). | Fidelity profoundly decreased (~10%). | Significant decrease (~3%). | |||||||||||
[ | ||||||||||||||
Slightly longer deletions. | [ | 71 | ] | |||||||||||
Mouse | slip | A transgene inserted by > 20 copies to upstream of three exons corresponding to 777–1010 nucleotides of mRNA. | mRNA undetectable; |
Late embryonic lethality (>E13.5)Kinase activity undetectable. | Reduced body size in uterus. | |||||||||
P5 | F | Severely defective; Massive cell death. | SCID; SJ & CJ: defective. | [ | Turkish | 109] | ||||||||
HMZ | c.6338del3, p.G2113del/ | c.T9185G, p.L3062R. |
SCID; Granuloma; Arthritis. | 70 | SCID; Increased thymic lymphomas. | ] | Not described. | [85][86][ | Not described. | 71] | ||||
[ | 118 | ] | XR-C1 | Hamster | ArtemisOvary | Unknown. | Protein undetectable; Kinase activity undetectable. |
Increased IR- and drug (bleomycin and ethyl methane sulfonate) sensitivity; Defective V(D)J recombination. | ||||||
XR-C1 | ||||||||||||||
[ | ||||||||||||||
Significant decrease (~2%). | Correct joins absent (0%). | |||||||||||||
72 | ||||||||||||||
Significant decrease (~2%). | ||||||||||||||
] | ||||||||||||||
Not described. | [ | |||||||||||||
Mouse, KD | −/− | |||||||||||||
72 | ] | |||||||||||||
c.A11765C, | p.D3922A. (4128 aa) |
Protein expression normal; Kinase activity undetectable. |
Viable.Embryonic lethal (E14.5); Defective neuronal development. | Normal body size.Increased IR-sensitivity; Increased genomic instability; Defective V(D)J recombination (CJ and SJ). | Normal. | [87 | SCID (leaky); SJ: normal; CJ: impaired. | ] | [110] | |||||
P6 | F | Turkish | HMZ c.6338del3, p.G2113del/ c.T9185G, p.L3062R. |
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. | |||||
XR-C2 | ||||||||||||||
[ | ||||||||||||||
Mild decrease (~30%). | Not described. | Mild decrease (~50%). | ||||||||||||
Mouse, | ||||||||||||||
Not described. | ||||||||||||||
3A | ||||||||||||||
[ | 73 | ] | ||||||||||||
c.A7813/7900 | /7927G p.T2605/2634/2643A. (4128 aa) | 73 | ] | Protein expression normal; | XLF | −/− | [74] | |||||||
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. | 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] |
SCID; Granuloma; Diarrhea. | ||||||||||||
Not described. | ||||||||||||
[ | ||||||||||||
118 | ||||||||||||
] | ||||||||||||
Increased sensitivity to IR, UV, CPT and MMC. | [ | 88 | ] | |||||||||
(Generated by gene targeting or genome editing) | ||||||||||||
xrs6 ( Ku80) |
Significant decrease (~5%). | Fidelity profoundly decreased (~15%). | Significant decrease (~1%). | None recovered. | [ | 81 | ] | |||||
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] | DT40 | Chicken | B lymphocyte | p. 2888–3012. (4133 aa) |
Protein undetectable. | Normal proliferation; Increased IR-sensitivity. | [75] |
XR-V15B (-Ku80) |
Undetectable (<1%). | |||||||||||
Horse SCID | ||||||||||||
Not described. | ||||||||||||
(Arabian foal) | ||||||||||||
Undetectable (<1%). | Not described. | |||||||||||
c.9478del5, p.S3160Nfs4*. | (4134 aa) |
Protein undetectable; Kinase activity undetectable. |
SCID. | |||||||||
[ | ||||||||||||
Increased IR-sensitivity; Defective V(D)J recombination (CJ and SJ). | ||||||||||||
19 | ] | |||||||||||
[ | 92 | ] | [ | 93 | ][94] | HCT116 | Human | Colon cancer | ||||
Dog SCID (Jack Russel Terriers) | p. 3831–4127. | (4128 aa) | Protein undetectable; Kinase activity undetectable. |
c.G10879A, p.E3627X.Reduced proliferation; Increased IR-, drug (etoposide)-sensitivity; Telomere shortening; Increased chromosomal aberrations. | (4144 aa) | [76] | ||||||
TK6 | Human | Increased drug (Etoposide)-sensitivity. | [ | 78 | ] | |||||||
Protein undetectable; | DNA binding barely detectable; |
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 | ||||||||
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. | ||
---|---|---|---|---|---|---|---|---|
Kinase activity undetectable. | ||||||||
SCID. | ||||||||
Increased IR-sensitivity; Defective V(D)J recombination (CJ and SJ). | ||||||||
[ | ||||||||
95 | ||||||||
] | ||||||||
[ | 96 | ] | ||||||
B lymphocyte | Part of exon 32 replaced with drug resistance gene. | Protein undetectable. | Increased IR-sensitivity. | |||||
Rat, gene knockout | Deletion in exon 1, causing frame-shift. | [ | 77 | ] | ||||
(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] | HAP1 | Human | Fibroblast-like, near haploid | |
Zebrafish, gene knockout | Frame-shift in exon 3. (4119 aa) | 11 bp deletion in exon 25. | Protein undetectable. | 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] |