The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient’s primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation’s aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria.

中文翻译：

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MDM2 / p53轴功能异常与过早老化有关

E3泛素连接酶MDM2通过自动调节反馈回路严格控制肿瘤抑制因子p53，它是细胞对应激反应的主要调节因子。除了在肿瘤发生中已确立的作用外，p53还与小鼠衰老有关。具有异常增加的p53活性的几种小鼠模型显示过早衰老的迹象。但是，MDM2 / p53轴功能障碍与人类衰老之间的关系仍然难以捉摸。在这里，我们已经确定了MDM2中的抗终止纯合种系突变患有节段性早熟综合征的患者。我们表明，这种突变消除了MDM2的活性，从而导致增强的p53水平和稳定性。对患者的原代细胞，基因组编辑的细胞以及体外和体内分析的分析证实了MDM2突变对p53活性的异常调节。斑马鱼模型的功能数据进一步证明，突变体Mdm2无法挽救p53诱导的细胞凋亡表型。总之，我们的发现表明，突变体MDM2可能是观察到的早衰节段形式的驱动因素。