Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells.
DDB1, a component of the Cul4 ubiquitin ligase complex, promotes protein ubiquitination in diverse cellular functions, including nuclear excision repair, regulation of the cell cycle, and DNA replication. To investigate its physiological significance, we generated mice with null and floxed alleles of the DDB1 gene. Here we report that null mutation of DDB1 caused early embryonic lethality, while conditional inactivation of the gene in brain and lens led to neuronal and lens degeneration, brain hemorrhages, and neonatal death. These defects stemmed from a selective elimination of nearly all proliferating neuronal progenitor cells and lens epithelial cells by apoptosis. The cell death was preceded by aberrant accumulation of cell cycle regulators and increased genomic instability and could be partially rescued by removal of the tumor suppressor protein p53. Our results indicate that DDB1 plays an essential role in maintaining viability and genomic integrity of dividing cells.
Cang
Yong
Y
Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Zhang
Jianxuan
J
Nicholas
Sally A
SA
Bastien
Jayson
J
Li
Baojie
B
Zhou
Pengbo
P
Goff
Stephen P
SP
D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D047108:Embryonic Development; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D018390:Gene Targeting; D006470:Hemorrhage / Q000473:pathology; D007908:Lens, Crystalline / Q000002:abnormalities / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008938:Mitosis; D009474:Neurons / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; C498645:Ris2 protein, mouse; D016159:Tumor Suppressor Protein p53