Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging.
Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging.
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DOI：
10.18632/oncotarget.7864
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Gu W
中科院分区：
文献类型：
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作者：
Li T;Liu X;Jiang L;Manfredi J;Zha S;Gu W
尽管p53介导的细胞周期阻滞、衰老和凋亡被广泛认为是主要的肿瘤抑制机制，但这些功能的丧失并不直接导致肿瘤发生，这表明p53这些典型活性的确切作用需要重新定义。在这里，我们报道了来自表达p533KR的突变小鼠的细胞，p533KR是一种乙酰化缺陷突变体，不能诱导细胞周期阻滞、衰老和凋亡，在DNA损伤时表现出高水平的非整倍体。此外，DNA双链断裂修复关键因子XRCC4缺失导致的胚胎致死性在p533KR/3KR背景下可以得到充分的挽救。值得注意的是，尽管基因组高度不稳定，但与p53 - / - XRCC4 - / -小鼠不同，p533KR/3KRXRCC4 - / -小鼠不会屈服于前b细胞淋巴瘤。然而，p533KR/3KR XRCC4 - / -小鼠表现出衰老样表型，包括睾丸萎缩、后凸和过早死亡。进一步分析表明，SLC7A11下调，p53介导的铁下垂在p533KR/3KRXRCC4−/−小鼠的脾脏和睾丸中显著诱导。这些结果表明，p53介导的细胞周期阻滞、衰老和凋亡的直接作用是控制体内基因组的稳定性。我们的研究不仅验证了铁下垂在p53介导的体内肿瘤抑制中的重要性，而且揭示了基因组不稳定性和铁下垂激活的结合可能促进衰老相关表型。
Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p533KR/3KR background. Notably, despite high levels of genomic instability, p533KR/3KRXRCC4−/− mice, unlike p53−/− XRCC4−/− mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p533KR/3KR XRCC4−/− mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p533KR/3KRXRCC4−/− mice. These results demonstrate that the direct role of p53-mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo. Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes.