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与端粒DNA结合的人类端粒酶全酶结构获解析
2021-04-25 13:00

英国医学研究理事会分子生物学实验室Thi Hoang Duong Nguyen课题组解析出与端粒DNA结合的人类端粒酶全酶结构。2021年4月21日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示,端粒酶在染色体末端添加端粒重复序列,从而补偿由不完整的基因组末端复制引起的端粒丢失。在人类中,端粒酶在胚胎发生和癌症中被上调,而损害端粒酶功能的突变会导致疾病。人类端粒酶的早期结构(分辨率为8Å)揭示了脊椎动物特有的组成和结构,其包含一个催化核心,该核心通过端粒酶RNA灵活地束缚在H和ACA(简称为H/ACA)核糖核蛋白(RNP)上。高分辨率的结构信息对于开发有效调节端粒酶活性的治疗方法是必不可少的,这是一种针对癌症和疾病的治疗方法。

研究人员使用冷冻电镜确定了端粒酶全酶的结构,该端粒酶以低于4Å的分辨率与端粒DNA结合,并揭示了端粒酶活性位点中至关重要的DNA和RNA结合界面以及改变端粒酶活性的突变位点。研究人员在全酶中鉴定了一个组蛋白H2A–H2B二聚体,该二聚体与必不可少的端粒酶RNA基序结合,这暗示了组蛋白在端粒酶RNA折叠和功能中的作用。此外,真核H/ACA RNP的这种结构揭示了保守RNA和蛋白质基序的分子识别,以及对于理解许多引起疾病的突变至关重要。这个发现提供了人类端粒酶装配和活性位点的结构细节,这为开发靶向该酶的治疗剂铺平了道路。 

附:英文原文

Title: Structure of human telomerase holoenzyme with bound telomeric DNA

Author: George E. Ghanim, Adam J. Fountain, Anne-Marie M. van Roon, Ramya Rangan, Rhiju Das, Kathleen Collins, Thi Hoang Duong Nguyen

Issue&Volume: 2021-04-21

Abstract: Telomerase adds telomeric repeats at chromosome ends to compensate for the telomere loss that is caused by incomplete genome end replication1. In humans, telomerase is upregulated during embryogenesis and in cancers, and mutations that compromise the function of telomerase result in disease2. A previous structure of human telomerase at a resolution of 8 revealed a vertebrate-specific composition and architecture3, comprising a catalytic core that is flexibly tethered to an H and ACA (hereafter, H/ACA) box ribonucleoprotein (RNP) lobe by telomerase RNA. High-resolution structural information is necessary to develop treatments that can effectively modulate telomerase activity as a therapeutic approach against cancers and disease. Here we used cryo-electron microscopy to determine the structure of human telomerase holoenzyme bound to telomeric DNA at sub-4 resolution, which reveals crucial DNA- and RNA-binding interfaces in the active site of telomerase as well as the locations of mutations that alter telomerase activity. We identified a histone H2A–H2B dimer within the holoenzyme that was bound to an essential telomerase RNA motif, which suggests a role for histones in the folding and function of telomerase RNA. Furthermore, this structure of a eukaryotic H/ACA RNP reveals the molecular recognition of conserved RNA and protein motifs, as well as interactions that are crucial for understanding the molecular pathology of many mutations that cause disease. Our findings provide the structural details of the assembly and active site of human telomerase, which paves the way for the development of therapeutic agents that target this enzyme.

DOI: 10.1038/s41586-021-03415-4

Source: https://www.nature.com/articles/s41586-021-03415-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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