Institute of Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, University of Rostock, Rostock, Germany.
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Berlin, Germany.
Sci Adv. 2022 Aug 19;8(33):eabk2814. doi: 10.1126/sciadv.abk2814. Epub 2022 Aug 17.
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 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.
端粒是每条染色体末端的重复核苷酸序列。人们假设，端粒磨损是大型长寿物种中的一种肿瘤抑制机制进化而来的。通过一种称为长距离端粒位置效应（TPE-OLD）的环化机制，长端粒可以沉默数百万个碱基远处的基因。这种沉默机制的功能尚不清楚。我们确定了一组在复制衰老物种中具有高度位置保守性的 2322 个基因，其中包括已知和候选的 TPE-OLD 基因，这些基因可能减轻复制衰老的潜在有害影响。值得注意的是，我们鉴定出作为一种肿瘤抑制基因，其在衰老的人成纤维细胞中通过 TPE-OLD 的上调导致 p70S6 激酶的去磷酸化和哺乳动物雷帕霉素靶蛋白的抑制。端粒与肿瘤抑制机制之间的机制联系支持这样一种假设，即复制性衰老发挥了肿瘤抑制功能，并激发了以前未知的抗肿瘤和抗衰老策略。
