Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53.
Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53.
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DOI：
10.1038/ng.441
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发表时间：
2009-10
期刊：
影响因子：
30.8
通讯作者：
Brown EJ
中科院分区：
文献类型：
--
作者：
Ruzankina Y;Schoppy DW;Asare A;Clark CE;Vonderheide RH;Brown EJ
Trp 53（p53）功能丧失先前已被证明可以挽救由DNA损伤或DNA修复基因突变引起的组织维持和发育缺陷。在此，我们报告说，p53缺陷显着加剧组织变性所造成的镶嵌删除的必要基因组维持调节ATR。ATR和p53的联合缺失（p53−/−ATRmKO）导致成年小鼠毛囊再生严重缺陷、局部炎症（Mac 1 + Gr 1+浸润）、肠上皮加速恶化和合成性致死。p53−/−ATRmKO小鼠的组织变性特征是细胞积累，维持高水平的DNA损伤。此外，这些受损细胞在皮肤中的祖细胞和下游隔室中的存在增加与来自残余ATR表达细胞的补偿性组织更新延迟相一致。总之，我们的研究结果表明，在成年小鼠中ATR和p53的组合损失导致高度受损细胞的积累，从而对未受损祖细胞的再生施加障碍。
Trp53 (p53) loss of function has previously been shown to rescue tissue maintenance and developmental defects resulting from DNA damage or DNA repair gene mutations. Herein, we report that p53 deficiency significantly exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator ATR. Combined loss of ATR and p53 (p53−/−ATRmKO) led to severe defects in hair follicle regeneration, localized inflammation (Mac1+Gr1+ infiltrates), accelerated deterioration of the intestinal epithelium, and synthetic lethality in adult mice. Tissue degeneration in p53−/−ATRmKO mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated presence of these damaged cells in both progenitor and downstream compartments in the skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. Together, our results indicate that combined loss of ATR and p53 in adult mice leads to the accumulation of highly damaged cells, which consequently impose a barrier to regeneration from undamaged progenitors.
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