The mammalian telomeric shelterin complex—comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1—blocks the DNA damage response at chromosome ends and interacts with telomerase and the CST complex to regulate telomere length. The evolutionary origins of shelterin are unclear, partly because unicellular organisms have distinct telomeric proteins. Here, we describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor. TRF1 and TRF2 diverged rapidly during vertebrate evolution through the acquisition of new domains and interacting factors. Vertebrate shelterin is also distinguished by the presence of an HJRL domain in the split C-terminal OB fold of POT1, whereas invertebrate POT1s carry inserts of variable nature. Importantly, the data reveal that, apart from the primate and rodent POT1 orthologs, all metazoan POT1s are predicted to have a fourth OB fold at their N termini. Therefore, we propose that POT1 arose from a four-OB-fold ancestor, most likely an RPA70-like protein. This analysis provides insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins.

中文翻译：

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后生动物庇护素的进化

由 TRF1、TRF2、Rap1、TIN2、TPP1 和 POT1 组成的哺乳动物端粒遮蔽蛋白复合物可阻断染色体末端的 DNA 损伤反应，并与端粒酶和 CST 复合物相互作用以调节端粒长度。庇护素的进化起源尚不清楚，部分原因是单细胞生物具有不同的端粒蛋白。在这里，我们描述了后生动物庇护素的进化，表明 TRF1 是在 TRF2 样祖先复制后出现在脊椎动物中的。TRF1 和 TRF2 在脊椎动物进化过程中通过获得新的结构域和相互作用因子迅速分化。脊椎动物shelterin的特点还在于在POT1的分裂C端OB折叠中存在HJRL结构域，而无脊椎动物POT1携带可变性质的插入物。重要的是，数据显示，除了灵长类动物和啮齿类动物 POT1 直系同源物外，所有后生动物 POT1 预计在其 N 末端有第四个 OB 折叠。因此，我们提出 POT1 起源于一个 4 倍 OB 的祖先，很可能是一种 RPA70 样蛋白。该分析提供了对shelterin生物学及其从祖先端粒DNA结合蛋白进化的见解。