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由CST蛋白复合物组织的端粒复制子的重建
2022-07-16 21:29

美国科罗拉多大学博尔德分校Thomas R. Cech团队近期取得重要工作进展,他们研究发现了由CST蛋白复合物组织的端粒复制子的重建。该项研究成果2022年7月13日在线发表于《自然》杂志上。

研究人员发现人类CST使用其ssDNA结合的活性来指定端粒C链合成的起源,并与Polα-primase结合。CST组织的DNA聚合可以复制折叠成G-四链体结构的端粒DNA模板,但该模板带来的挑战可能会导致体内观察到的端粒复制问题。结合端粒酶、短端粒ssDNA引物和CST-Polα-primase可提供完整的端粒DNA复制,从而产生与人类端粒上天然存在的相同类型的ssDNA 3'突出。研究人员得出结论,CST复合物不仅终止端粒酶延伸并将Polα-primase募集到端粒ssDNA,而且还协调C链的合成。由于端粒的复制具有与基因组其余部分的复制不同的特征,因此靶向包括CST在内的端粒复制成分有望用于癌症治疗。

据介绍,端粒是线性染色体的自然末端,由重复DNA序列和相关蛋白质组成。端粒的复制可以使人类干细胞持续增殖,使癌细胞永生。这种复制需要端粒G链((TTAGGG)n)的单链DNA(ssDNA)的端粒酶延伸;互补C链((CCCTAA)n)合成的特征要少得多。CST(CTC1-STN1-TEN1)蛋白复合物是一种DNA聚合酶α-引物辅助因子,已知是体内端粒复制所必需的,本文的分子分析揭示了其机制的关键特征。

附:英文原文

Title: Reconstitution of a telomeric replicon organized by CST

Author: Zaug, Arthur J., Goodrich, Karen J., Song, Jessica J., Sullivan, Ashley E., Cech, Thomas R.

Issue&Volume: 2022-07-13

Abstract: Telomeres, the natural ends of linear chromosomes, comprise repeat-sequence DNA and associated proteins1. Replication of telomeres allows continued proliferation of human stem cells and immortality of cancer cells2. This replication requires telomerase3 extension of the single-stranded DNA (ssDNA) of the telomeric G-strand ((TTAGGG)n); the synthesis of the complementary C-strand ((CCCTAA)n) is much less well characterized. The CST (CTC1–STN1–TEN1) protein complex, a DNA polymerase α-primase accessory factor4,5, is known to be required for telomere replication in vivo6,7,8,9, and the molecular analysis presented here reveals key features of its mechanism. We find that human CST uses its ssDNA-binding activity to specify the origins for telomeric C-strand synthesis by bound Polα-primase. CST-organized DNA polymerization can copy a telomeric DNA template that folds into G-quadruplex structures, but the challenges presented by this template probably contribute to telomere replication problems observed in vivo. Combining telomerase, a short telomeric ssDNA primer and CST–Polα–primase gives complete telomeric DNA replication, resulting in the same sort of ssDNA 3′overhang found naturally on human telomeres. We conclude that the CST complex not only terminates telomerase extension10,11 and recruits Polα–primase to telomeric ssDNA4,12,13 but also orchestrates C-strand synthesis. Because replication of the telomere has features distinct from replication of the rest of the genome, targeting telomere-replication components including CST holds promise for cancer therapeutics.

DOI: 10.1038/s41586-022-04930-8

Source: https://www.nature.com/articles/s41586-022-04930-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
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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