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


Authors: Stracker, T. H.; Williams, B. R.; Deriano, L.; Theunissen, J. W.; Adelman, C. A.; Roth, D. B.; Petrini, J. H. J.
Article Title: Artemis and nonhomologous end joining-independent influence of DNA-dependent protein kinase catalytic subunit on chromosome stability
Abstract: 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(Delta B) allele permitted viability of some Nbs1(Delta B/Delta B) Prkdc(scid/scid) embryos. Cell cultures from Nbs1(Delta B/Delta B) 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.
Keywords: neurogenesis; recombination; saccharomyces-cerevisiae; strand break repair; mre11 complex; atm activation; ligase iv deficiency; homologous; defective; mammalian telomeres; v(d)j recombination; damage response
Journal Title: Molecular and Cellular Biology
Volume: 29
Issue: 2
ISSN: 0270-7306
Publisher: American Society for Microbiology  
Date Published: 2009-01-01
Start Page: 503
End Page: 514
Language: English
ACCESSION: ISI:000262045800018
DOI: 10.1128/mcb.01354-08
PROVIDER: wos
PMCID: PMC2612508
PUBMED: 19015239
Notes: --- - Article - "Source: Wos"
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  1. John Petrini
    76 Petrini