The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants.
There are two general pathways by which multicellular eukaryotes repair double-strand DNA breaks (DSB): homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). All mammalian mutants in the NHEJ pathway demonstrate a lack of B and T lymphocytes and ionizing radiation sensitivity. Among these NHEJ mutants, the DNA-PK(cs) and Artemis mutants are the least severe, having no obvious phenotype other than the general defects described above. Ku mutants have an intermediate severity with accelerated senescence. The XRCC4 and DNA ligase IV mutants are the most severe, resulting in embryonic lethality. Here we show that the lethality of DNA ligase IV-deficiency in the mouse can be rescued when Ku86 is also absent. To explain the fact that simultaneous gene mutations in the NHEJ pathway can lead to viability when a single mutant is not viable, we propose a nuclease/ligase model. In this model, disrupted NHEJ is more severe if the Artemis:DNA-PK(cs) nuclease is present in the absence of a ligase, and Ku mutants are of intermediate severity, because the nuclease is less efficient. This model is also consistent with the order of severity in organismal phenotypes; consistent with chromosomal breakage observations reported here; and consistent with the NHEJ mutation identified in radiation sensitive human SCID patients.
Karanjawala
Zarir E
ZE
Norris Comprehensive Cancer Center, Rm 5428, Department of Pathology, University of Southern California, Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Adachi
Noritaka
N
Irvine
Ryan A
RA
Oh
Eui K
EK
Shibata
Darryl
D
Schwarz
Klaus
K
Hsieh
Chih-Lin
CL
Lieber
Michael R
MR
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics; D002478:Cells, Cultured; D019457:Chromosome Breakage; D004265:DNA Helicases; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency* / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005313:Fetal Death / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D011995:Recombination, Genetic
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606512:Xrcc5 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP