Artemis and Nonhomologous End Joining-Independent Influence of DNA-Dependent Protein Kinase Catalytic Subunit on Chromosome Stability▿ †

摘要

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 (Mre11ATLD1) led to synthetic lethality when juxtaposed with DNA-PKcs deficiency (Prkdcscid). In contrast, the more moderate DNA double-strand break response defects associated with the Nbs1ΔB allele permitted viability of some Nbs1ΔB/ΔB Prkdcscid/scid embryos. Cell cultures from Nbs1ΔB/ΔB Prkdcscid/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/G2-phase chromosome stability and in the induction of cell cycle checkpoint responses.