Table 1 Summary of currently available ATM, ATR and DNA-PKcs mouse models
From: ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion
Mouse models | Mutations | Fitness | Fertility | Main phenotypes | References |
|---|---|---|---|---|---|
DNA-PKcs | |||||
DNA-PKcs−/− | Null/knockout | Viable | Fertile | SCID; T and B cells developmental blockade; defective coding joint formation | Taccioli et al. [188], Gao et al. [49]; Kurimasa et al. [50] |
DNA-PKcs3A/3A | Knockin, T2605/T2634/T2643A, phosphorylation site mutations | Viable | ND | Small; p53 dependent bone marrow failure; early lethality (2–3 weeks old) | Zhang et al. [74] |
DNA-PKcsKD/KD and | Knockin, kinase dead DNA-PKcs (D3922A) | Embryonic lethal (E16.5) | ND | SJ and CJ fomation blocked; CSR defects; embryonic lethality rescued by KU deletion | |
DNA-PKcsKD/−* | |||||
DNA-PKcsPQR/PQR | Knockin, S2053 cluster mutated to Alanine | Viable | Fertile | Normal CSR and V(D)J recombination; moderate IR sensitivity | Jiang et al. [73] |
DNA-PKcsSD/SD | Knockin, S2053 cluster mutated to Aspartate | Viable | Fertile | Normal CSR and V(D)J recombination | Jiang et al. [73] |
ATM | |||||
Atm−/− | Null/knockout | Viable | Infertile | Growth retardation; lack of mature gametes; T cells deficiency and thymic lymphomas | Barlow et al. [91], Elson et al. [92], Xu et al. [93], Borghesani et al. [94] |
AtmTgS1987A and AtmTgS1987A/S367A/S1899A | BAC transgene, S1987A or S1987A/S367A/A1899A, phosphorylation site mutations | Viable | Fertile | No major phenotypes; proper DDR | |
AtmKD/KD and AtmKD/−** | Knockin, kinase dead ATM (D2880A, N2885K) | Embryonic lethal (E9.5) | ND | Severe genomic instability; hyper sensitivity to Topoisomerase I inhibitors and pro-cancer | |
AtmTgD2899A Atm−/− and AtmTgQ2740P Atm−/− | BAC transgene, kinase dead ATM (D2899A, Q2740P) | Embryonic lethal (< E12.5) | ND | Severe genomic instability, PARP inhibitor sensitivity | Daniel et al. [19] |
ATR | |||||
Atr−/− | Null/knockout | Embryonic lethal (< E7.5) | ND | Chromosome fragmentation at blastocyst stage | Brown et al. [125] |
de Klein et al. [146], | |||||
AtrSeckel/Seckel | Seckel mutation (exons 8–10 replaced by human sequence with A ≥ G substitution in exon 9) | Viable | Fertile | Craniofacial abnormalities; growth retardation; embryonic replicative stress; accelerated aging | Murga et al. [152] |
Atr +/KD | Knockin, kinase dead ATR (D2466A) | Viable | Male infertility | Male spermatogenesis defects, mild lymphocytopenia | Menolfi et al. [21] |
AtrKD/−*** | Knockin, kinase dead ATR (D2466A) | Embryonic lethal (< E9) | ND | Early embryonic lethality | Menolfi et al. [21] |