DNA Ligase IV Deficiency in Mice Leads to Defective Neurogenesis and Embryonic Lethality via the p53 Pathway

DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair. In mice, Lig4 deficiency causes embryonic lethality, massive neuronal apoptosis, arrested lymphogenesis, and various cellular defects. Herein, we assess potential roles in this phenotype f...

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Bibliographic Details
Published in:Molecular cell 2000-06, Vol.5 (6), p.993-1002
Main Authors: Frank, Karen M, Sharpless, Norman E, Gao, Yijie, Sekiguchi, JoAnn M, Ferguson, David O, Zhu, Chengming, Manis, John P, Horner, James, DePinho, Ronald A, Alt, Frederick W
Format: Article
Language:English
Subjects:
Animals
Apoptosis
ARF protein
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Division
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p16
DNA Ligase ATP
DNA ligase IV
DNA Ligases - deficiency
DNA Ligases - genetics
DNA Ligases - metabolism
Fetal Death
Fibroblasts - cytology
Fibroblasts - metabolism
Gene Deletion
Genotype
INK4a protein
Lig4 gene
Lymphocytes - cytology
Lymphocytes - metabolism
Lymphocytes - radiation effects
Lymphoma, B-Cell - pathology
Mice
Mice, Knockout
Neurons - cytology
Neurons - metabolism
p53 gene
Phenotype
Radiation Tolerance
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair. In mice, Lig4 deficiency causes embryonic lethality, massive neuronal apoptosis, arrested lymphogenesis, and various cellular defects. Herein, we assess potential roles in this phenotype for INK4a/ARF and p53, two proteins implicated in apoptosis and senescence. INK4a/ARF deficiency rescued proliferation/senescence defects of Lig4-deficient fibroblasts but not other phenotypic aspects. In contrast, p53 deficiency rescued embryonic lethality, neuronal apoptosis, and fibroblast proliferation/senescence defects but not lymphocyte development or radiosensitivity. Young Lig4/p53 double null mice routinely died from pro-B lymphomas. Thus, in the context of Lig4 deficiency, embryonic lethality and neuronal apoptosis likely result from a p53-dependent response to unrepaired DNA damage, and neuronal apoptosis and lymphocyte developmental defects can be mechanistically dissociated.
ISSN:1097-2765
1097-4164
DOI:10.1016/S1097-2765(00)80264-6