TY - JOUR
T1 - DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway
AU - Frank, Karen M.
AU - Sharpless, Norman E.
AU - Gao, Yijie
AU - Sekiguchi, Jo Ann M.
AU - Ferguson, David O.
AU - Zhu, Chengming
AU - Manis, John P.
AU - Horner, James
AU - DePinho, Ronald A.
AU - Alt, Frederick W.
N1 - Funding Information:
We thank Allen Bradley for the probe for p53 Southern analysis and S. Artandi for critical reading of the manuscript. This work was supported by National Institutes of Health grants AI20047 and AI35714 (F. W. A.), AI01428 (K. M. F.), R01HD34880 and R01HD28317 (R. P.), and a Hood Foundation grant (J. P. M.). J. M. S. is the Richard D. Frisbee III Foundation Fellow of the Leukemia Society of America. N. E. S. is a Physician Postdoctoral Fellow, Y. G., Associate, and F. W. A., an Investigator of the Howard Hughes Medical Institute. R. A. D. is a American Cancer Society Research Professor.
PY - 2000
Y1 - 2000
N2 - 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 phenotypes 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.
AB - 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 phenotypes 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.
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U2 - 10.1016/S1097-2765(00)80264-6
DO - 10.1016/S1097-2765(00)80264-6
M3 - Article
C2 - 10911993
AN - SCOPUS:0033634973
SN - 1097-2765
VL - 5
SP - 993
EP - 1002
JO - Molecular cell
JF - Molecular cell
IS - 6
ER -