Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/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.
Theunissen
Jan-Willem F
JW
Molecular Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, NY 10021, USA.
Kaplan
Mark I
MI
Hunt
Patricia A
PA
Williams
Bret R
BR
Ferguson
David O
DO
Alt
Frederick W
FW
Petrini
John H J
JH
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D043171:Chromosomal Instability; D033481:Chromosomes, Mammalian / Q000378:metabolism*; D004249:DNA Damage; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000502:physiology; D005260:Female; D005298:Fertility; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D018816:Genes, cdc; D006801:Humans; D007621:Karyotyping; D008223:Lymphoma / Q000378:metabolism*; D000076228:MRE11 Homologue Protein; D051379:Mice; D011247:Pregnancy; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; D016159:Tumor Suppressor Protein p53; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes