Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis |
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Authors: | Gurley K E Kemp C J |
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Institution: | Fred Hutchinson Cancer Research Center C1-015, 1100 Fairview Ave. N., Seattle, WA 90109-1024, USA. |
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Abstract: | 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 (PI3K)-related protein kinase superfamily, which includes the catalytic subunit of DNA-dependent protein kinase (DNA-PK(cs)) 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(cs) and, like Atm(-/-) mice, are viable and radiosensitive 4-8]. To determine if Atm and DNA-PK(cs) 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. |
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