Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
Laboratory of Molecular Genetics of Aging and Tumor, School of Medicine, Kunming University Science and Technology, Kunming, 650500, China.
Nat Commun. 2021 Sep 17;12(1):5514. doi: 10.1038/s41467-021-25799-7.
Human shelterin components POT1 and TPP1 form a stable heterodimer that protects telomere ends from ATR-dependent DNA damage responses and regulates telomerase-dependent telomere extension. Mice possess two functionally distinct POT1 proteins. POT1a represses ATR/CHK1 DNA damage responses and the alternative non-homologous end-joining DNA repair pathway while POT1b regulates C-strand resection and recruits the CTC1-STN1-TEN1 (CST) complex to telomeres to mediate C-strand fill-in synthesis. Whether POT1a and POT1b are involved in regulating the length of the telomeric G-strand is unclear. Here we demonstrate that POT1b, independent of its CST function, enhances recruitment of telomerase to telomeres through three amino acids in its TPP1 interacting C-terminus. POT1b thus coordinates the synthesis of both telomeric G- and C-strands. In contrast, POT1a negatively regulates telomere length by inhibiting telomerase recruitment to telomeres. The identification of unique amino acids between POT1a and POT1b helps us understand mechanistically how human POT1 switches between end protective functions and promoting telomerase recruitment.
人类端粒保护蛋白（shelterin）成分 POT1 和 TPP1 形成稳定的异二聚体，保护端粒末端免受 ATR 依赖性 DNA 损伤反应的影响，并调节端粒酶依赖性端粒延伸。小鼠拥有两种功能不同的 POT1 蛋白。POT1a 抑制 ATR/CHK1 DNA 损伤反应和非同源末端连接（NHEJ）DNA 修复途径，而 POT1b 调节 C 链切除，并招募 CTC1-STN1-TEN1（CST）复合物到端粒，以介导 C 链填充合成。POT1a 和 POT1b 是否参与调节端粒 G 链的长度尚不清楚。在这里，我们证明了 POT1b 独立于其 CST 功能，通过其与 TPP1 相互作用的 C 末端的三个氨基酸增强端粒酶向端粒的招募。因此，POT1b 协调了端粒 G 链和 C 链的合成。相比之下，POT1a 通过抑制端粒酶向端粒的招募来负调控端粒长度。在 POT1a 和 POT1b 之间识别出独特的氨基酸有助于我们从机制上理解人类 POT1 如何在端粒保护功能和促进端粒酶招募之间切换。
