美国洛克菲勒大学Titia de Lange等研究人员合作发现，POT1在人类端粒上招募并调控CST-Polα/引发酶。相关论文于2024年6月4日在线发表在《细胞》杂志上。

研究人员表示，端粒的维持需要端粒酶延长富含G的端粒重复链，以及Polα/引发酶填充合成富含C的端粒重复链。在端粒处，Polα/引发酶与单链DNA结合复合物Ctc1/Stn1/Ten1（CST）结合。与端粒酶突变一样，影响CST-Polα/引发酶的突变也会导致病理性端粒缩短，并引起端粒生物学紊乱，即Coats plus（CP）。

研究人员测定了人CST与shelterin异源二聚体POT1/TPP1结合的冷冻电镜结构，揭示了CST是如何被POT1招募到端粒上的。研究结果表明，POT1的铰链磷酸化是CST招募所必需的，并且该复合物是通过涉及CP中突变的几个残基的保守相互作用而形成的。结构和生化数据表明，磷酸化的POT1使CST-Polα/引发酶处于非活性的自动抑制状态，直到端粒酶延长了端粒末端。研究人员认为，POT1的去磷酸化会使CST-Polα/引发酶进入活性状态，从而通过填充合成完成端粒复制。

附：英文原文

Title: POT1 recruits and regulates CST-Polα/primase at human telomeres

Author: Sarah W. Cai, Hiroyuki Takai, Arthur J. Zaug, Teague C. Dilgen, Thomas R. Cech, Thomas Walz, Titia de Lange

Issue&Volume: 2024-06-04

Abstract: Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polα/primase. At telomeres, Polα/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/primase into an active state that completes telomere replication through fill-in synthesis.

DOI: 10.1016/j.cell.2024.05.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00493-8