MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge, UK.
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands.
Nat Commun. 2024 Mar 21;15(1):2518. doi: 10.1038/s41467-024-46844-1.
DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1 mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.
DNA 修复缺陷可导致人类和小鼠的节段性表型，其中某些组织失去内稳态，而其他组织似乎未受影响。这可能是由于不同组织面临不同程度的损伤，或者对特定的 DNA 修复途径有不同的依赖。然而，我们发现细胞对 DNA 损伤的反应决定了不同的组织特异性结果。在这里，我们使用由 DNA 修复缺失引起的人类 XPF-ERCC1 早老症（XFE）的小鼠模型。我们发现，p53 是细胞对 DNA 损伤反应的核心调节剂，以不同的方式调节 Ercc1 小鼠的组织功能障碍。我们表明，p53 的缺失可挽救造血干细胞的丧失，对肾脏、生殖细胞或大脑功能障碍没有影响，但会加重肝脏病理学和多倍体化。从机制上讲，我们发现 p53 的缺失导致肝脏中细胞周期调节丧失，p21 表达减少。最终，p16/Cdkn2a 的表达被诱导，作为在缺乏 p53-p21 轴的情况下增殖的失效安全制动。总之，我们的数据表明，p53 对 DNA 损伤的反应具有不同的组织特异性功能，在调节组织特异性表型方面发挥着关键作用。
