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.
Mesh Terms:
Animals, 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, G2 Phase, Mice, Mice, Transgenic, Nuclear Proteins, Protein-Serine-Threonine Kinases, S Phase, Tumor Suppressor Proteins
Mol. Cell. Biol.
Date: Jan. 01, 2009
Download Curated Data For This Publication
105271
Switch View:
  • Interactions 1