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Artemis and nonhomologous end joining-independent influence of DNA-dependent protein kinase catalytic subunit on chromosome stability.

Deficiency in both ATM and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is synthetically lethal in developing mouse embryos. Using mice that phenocopy diverse aspects of Atm deficiency, we have analyzed the genetic requirements for embryonic lethality in the absence of functional DNA-PKcs. Similar to the loss of ATM, hypomorphic mutations of Mre11 (Mre11(ATLD1)) led to synthetic lethality when juxtaposed with DNA-PKcs deficiency (Prkdc(scid)). In contrast, the more moderate DNA double-strand break response defects associated with the Nbs1(DeltaB) allele permitted viability of some Nbs1(DeltaB/DeltaB) Prkdc(scid/scid) embryos. Cell cultures from Nbs1(DeltaB/DeltaB) Prkdc(scid/scid) embryos displayed severe defects, including premature senescence, mitotic aberrations, sensitivity to ionizing radiation, altered checkpoint responses, and increased chromosome instability. The known functions of DNA-PKcs in the regulation of Artemis nuclease activity or nonhomologous end joining-mediated repair do not appear to underlie the severe genetic interaction. Our results reveal a role for DNA-PKcs in the maintenance of S/G(2)-phase chromosome stability and in the induction of cell cycle checkpoint responses.

Pubmed ID: 19015239


  • Stracker TH
  • Williams BR
  • Deriano L
  • Theunissen JW
  • Adelman CA
  • Roth DB
  • Petrini JH


Molecular and cellular biology

Publication Data

January 30, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM056888
  • Agency: NIGMS NIH HHS, Id: R01 GM059413

Mesh Terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Death
  • Chromosomal Instability
  • Chromosomal Proteins, Non-Histone
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • DNA Repair Enzymes
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins
  • Embryo, Mammalian
  • Endonucleases
  • G2 Phase
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases
  • S Phase
  • Tumor Suppressor Proteins