DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes.
Nonhomologous DNA end joining (NHEJ) is the major pathway for repairing double-strand DNA breaks. V(D)J recombination is a double-strand DNA breakage and rejoining process that relies on NHEJ for the joining steps. Here we show that the targeted disruption of both DNA ligase IV alleles in a human pre-B cell line renders the cells sensitive to ionizing radiation and ablates V(D)J recombination. This phenotype can only be reversed by complementation with DNA ligase IV but not by expression of either of the remaining two ligases, DNA ligase I or III. Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
Grawunder
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U
University of Southern California School of Medicine, Norris Comprehensive Cancer Center, Department of Pathology, Los Angeles 90033, USA.
Zimmer
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D
Fugmann
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S
Schwarz
K
K
Lieber
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MR
D000483:Alleles; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000528:radiation effects; D002478:Cells, Cultured; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D004254:DNA Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D018076:DNA, Complementary; D005816:Genetic Complementation Test; D006801:Humans; D016296:Mutagenesis / Q000502:physiology; D010641:Phenotype; D045567:VDJ Recombinases
D018076:DNA, Complementary; C000607892:LIG1 protein, human; C000607893:LIG4 protein, human; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases; D011088:DNA Ligases; D000072481:DNA Ligase ATP