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.
Stracker
Travis H
TH
Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, NY 10065, USA.
Williams
Bret R
BR
Deriano
Ludovic
L
Theunissen
Jan W
JW
Adelman
Carrie A
CA
Roth
David B
DB
Petrini
John H J
JH
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D043171:Chromosomal Instability; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004622:Embryo, Mammalian; D004720:Endonucleases; D016195:G2 Phase; D000076228:MRE11 Homologue Protein; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000098550:Structural Maintenance of Chromosome Protein 1
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D000098550:Structural Maintenance of Chromosome Protein 1; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases; D004720:Endonucleases; D000076228:MRE11 Homologue Protein; C473337:Dclre1c protein, mouse; D045643:DNA Repair Enzymes