Checkpoint Failure and Chromosomal Instability without Lymphomagenesis in Mre11ATLD1/ATLD1 Mice
Copyright policy )Checkpoint Failure and Chromosomal Instability without Lymphomagenesis in Mre11ATLD1/ATLD1 Mice
In this study, mice expressing one of the two Mre11 alleles inherited in the human ataxia-telangiectasia like disorder (A-TLD) were derived. The mutation had a profound maternal effect on embryonic viability, revealing an acute requirement for Mre11 complex function in early embryogenesis. Mre11(ATLD1/ATLD1) mice exhibited several indices of impaired ATM function. The mice also exhibited pronounced chromosomal instability. Despite this phenotypic spectrum, the animals were not prone to malignancy. These data indicate that defective cell cycle checkpoints and chromosomal instability are insufficient to significantly enhance the initiation of tumorigenesis. In contrast, the latency of malignancy in p53(+/-) mice was dramatically reduced. We propose that in Mre11(ATLD1/ATLD1) mice, genome instability and cell cycle checkpoint defects reduce viability in early embryos and in proliferating cells, while promoting malignancy in the context of an initiating lesion.
- University of Wisconsin–Madison United States
- Memorial Sloan Kettering Cancer Center United States
- Case Western Reserve University United States
- Washington State University United States
- Harvard University United States
Fibroblasts - physiology, Lymphoma, DNA-Binding Proteins - metabolism, Cells, Fibroblasts - cytology, Tumor Suppressor Protein p53 - metabolism, 610, Chromosomes, Lymphoma - metabolism, 576, Ataxia Telangiectasia, Mice, Pregnancy, Chromosomal Instability, Animals, Humans, Tumor Suppressor Protein p53 - genetics, cdc, Molecular Biology, Cells, Cultured, MRE11 Homologue Protein, Cultured, Cell Cycle, Cell Cycle - physiology, Cell Biology, Fibroblasts, Embryo, Mammalian, Chromosomes, Mammalian, Survival Rate, Mammalian - physiology, DNA-Binding Proteins, Genes, cdc, DNA-Binding Proteins - genetics, DNA Repair Enzymes, Fertility, Genes, Embryo, Karyotyping, Ataxia Telangiectasia - genetics, Female, Mammalian - metabolism, DNA Damage
Fibroblasts - physiology, Lymphoma, DNA-Binding Proteins - metabolism, Cells, Fibroblasts - cytology, Tumor Suppressor Protein p53 - metabolism, 610, Chromosomes, Lymphoma - metabolism, 576, Ataxia Telangiectasia, Mice, Pregnancy, Chromosomal Instability, Animals, Humans, Tumor Suppressor Protein p53 - genetics, cdc, Molecular Biology, Cells, Cultured, MRE11 Homologue Protein, Cultured, Cell Cycle, Cell Cycle - physiology, Cell Biology, Fibroblasts, Embryo, Mammalian, Chromosomes, Mammalian, Survival Rate, Mammalian - physiology, DNA-Binding Proteins, Genes, cdc, DNA-Binding Proteins - genetics, DNA Repair Enzymes, Fertility, Genes, Embryo, Karyotyping, Ataxia Telangiectasia - genetics, Female, Mammalian - metabolism, DNA Damage
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