Tissue Regenerative Delays and Synthetic Lethality in Adult Mice After Combined Deletion of ATR and TRP53

    August 2009 in “ Nature Genetics ”
    Yaroslava Ruzankina, David W. Schoppy, Amma Asare, Charles C. Clark, Robert H. Vonderheide, Eric J. Brown
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    TLDR Removing both Atr and Trp53 genes in adult mice causes severe tissue damage and death due to DNA damage.
    The study conducted 14 years ago demonstrated that the combined deletion of the Atr and Trp53 genes in adult mice resulted in severe tissue degeneration and defects in hair follicle regeneration, as well as accelerated deterioration of the intestinal epithelium and synthetic lethality. The absence of Trp53 exacerbated the lethal phenotype, with a mortality rate of over 94% within two weeks among Trp53-/-Atrmko mice. The degeneration was due to the accumulation of cells with high levels of DNA damage, which hindered regeneration from undamaged progenitors. The study highlighted the critical role of Trp53 in survival following Atr deletion and suggested that ATR-Chk1 inhibitors might be effective in treating Trp53-deficient cancers.
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