Synthetic lethality between mutation in Atm and DNA-PKcs during murine embryogenesis

The gene product mutated in ataxia telangiectasia, ATM, is a ubiquitously expressed 370 kDa protein kinase that is a key mediator of the cellular response to DNA damage [1], ATM-deficient cells are radiosensitive and show impaired cell cycle arrest and increased chromosome breaks in response to ionizing radiation. ATM is a member of the phosphatidylinositol-3-kinase (Pl3K)-related protein kinase superfamily, which includes the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and ATR [2], DNA-PK is a 470 kDa protein kinase that is required for proper end-to-end rejoining of DNA double-strand breaks [3], Prkdc(scid/scid) mice have a homozygous mutation in the gene encoding DNA-PK, and, like Atm(-/-) mice, are viable and radiosensitive [4-8], To determine if Atm and DNA-PK, show genetic interaction, we attempted to generate mice deficient in both gene products. However, no scid/scid Atm(-/-) pups were recovered from scid/scid Atm(-/-) intercrosses. Developmental arrest of scid/scid Atm(-/-) embryos occurred around E7.5, a developmental stage when embryonic cells are hypersensitive to DNA damage [9], This reveals synthetic lethality between mutations in Atm and DNA-PK and suggests that Atm and DNA-PK have complementary functions that are essential for development.