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 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.
Frank
K M
KM
Howard Hughes Medical Institute, Boston, Massachusetts, USA.
Sharpless
N E
NE
Gao
Y
Y
Sekiguchi
J M
JM
Ferguson
D O
DO
Zhu
C
C
Manis
J P
JP
Horner
J
J
DePinho
R A
RA
Alt
F W
FW
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005313:Fetal Death; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D011836:Radiation Tolerance; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D011088:DNA Ligases; D000072481:DNA Ligase ATP