Synthetic lethality between mutation in Atm and DNA-PK(cs) 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 (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.
Fred Hutchinson Cancer Research Center C1-015, 1100 Fairview Ave. N., Seattle, WA 90109-1024, USA.
K E
KE
Gurley
C J
CJ
Kemp
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D017931:DNA Primers; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005804:Genes, Lethal; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases