Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies.

中文翻译：

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一种保守的长距离端粒沉默机制抑制衰老人成纤维细胞中的 mTOR 信号

端粒是每条染色体末端的重复核苷酸序列。据推测，端粒损耗在大型长寿物种中进化为一种肿瘤抑制机制。长端粒可以通过称为长距离端粒位置效应 (TPE-OLD) 的循环机制使数百万个碱基之外的基因沉默。这种沉默机制的功能是未知的。我们确定了一组 2322 个在复制老化物种中具有高度位置保守性的基因，其中包括已知和候选的 TPE-OLD 基因，这些基因可能会减轻复制老化的潜在有害影响。值得注意的是，我们确定PPP2R2C作为肿瘤抑制基因，其在老年人成纤维细胞中被 TPE-OLD 上调导致 p70S6 激酶去磷酸化和雷帕霉素抑制的哺乳动物靶标。端粒和肿瘤抑制机制之间的机械联系支持复制老化实现肿瘤抑制功能并激发以前未知的抗肿瘤和抗衰老策略的假设。