Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis

Curr Biol. 2001 Feb 6;11(3):191-4. doi: 10.1016/s0960-9822(01)00048-3.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Cell Cycle Proteins
  • DNA Primers
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Genes, Lethal*
  • Mice
  • Mice, SCID
  • Mutation*
  • Nuclear Proteins
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases / genetics*
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • Protein-Serine-Threonine Kinases