小柯机器人

美国加州大学洛杉矶分校Juli Feigon、Z. Hong Zhou等研究人员合作揭示端粒重复合成几个步骤中端粒酶的结构。这一研究成果于2021年5月12日在线发表在国际学术期刊《自然》上。

研究人员报道了活性四膜虫端粒酶与端粒DNA在核苷酸添加不同步骤的冷冻电镜结构。端粒酶逆转录酶（TERT）、端粒酶RNA（TER）和DNA之间的相互作用揭示了核苷酸添加过程中5'和3'模板边界确定、模板-DNA双链体加工和产物链分离的结构基础。TERT和端粒酶蛋白p50（人类TPP1的同源物）之间的结构和结合界面定义了端粒酶激活和招募到端粒所需的保守相互作用。端粒酶La相关蛋白p65重塑TER的几个区域，桥接5'和3'末端以及保守的假结，从而促进TERT–TER催化核心的组装。

据悉，端粒酶在逆转录酶中是独特的，它包含一个非编码RNA（称为端粒酶RNA），该RNA包括一个短模板，用于在大多数真核染色体3'端进行富含G的端粒DNA重复序列合成。端粒酶维持基因组完整性，其活性或失调是人类寿命、干细胞更新和癌症进展的关键决定因素。先前的冷冻电镜结构已经确定了四膜虫和人类端粒酶的一般结构、蛋白质成分和化学计量，但是人们对DNA-蛋白质和RNA-蛋白质相互作用的细节以及涉及的机制和招募的理解仍然有限。

附：英文原文

Title: Structures of telomerase at several steps of telomere repeat synthesis

Author: Yao He, Yaqiang Wang, Baocheng Liu, Christina Helmling, Lukas Suac, Ryan Cheng, Z. Hong Zhou, Juli Feigon

Issue&Volume: 2021-05-12

Abstract: Telomerase is unique among the reverse transcriptases in containing a noncoding RNA (known as telomerase RNA (TER)) that includes a short template that is used for the processive synthesis of G-rich telomeric DNA repeats at the 3′ ends of most eukaryotic chromosomes1. Telomerase maintains genomic integrity, and its activity or dysregulation are critical determinants of human longevity, stem cell renewal and cancer progression2,3. Previous cryo-electron microscopy structures have established the general architecture, protein components and stoichiometries of Tetrahymena and human telomerase, but our understandings of the details of DNA–protein and RNA–protein interactions and of the mechanisms and recruitment involved remain limited4,5,6. Here we report cryo-electron microscopy structures of active Tetrahymena telomerase with telomeric DNA at different steps of nucleotide addition. Interactions between telomerase reverse transcriptase (TERT), TER and DNA reveal the structural basis of the determination of the 5′ and 3′ template boundaries, handling of the template–DNA duplex and separation of the product strand during nucleotide addition. The structure and binding interface between TERT and telomerase protein p50 (a homologue of human TPP17,8) define conserved interactions that are required for telomerase activation and recruitment to telomeres. Telomerase La-related protein p65 remodels several regions of TER, bridging the 5′ and 3′ ends and the conserved pseudoknot to facilitate assembly of the TERT–TER catalytic core.

DOI: 10.1038/s41586-021-03529-9

Source: https://www.nature.com/articles/s41586-021-03529-9

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