人类复制体引导一种专用于前导链的引物酶促进复制叉重启
人类复制体引导一种专用于前导链的引物酶促进复制叉重启
作者： 小柯机器人 发布时间：2026/11/12 19:53:55
本期文章：《自然》：Online/在线发表
英国MRC分子生物学实验室研究团队近日取得一项新成果。经过不懈努力，他们的最新研究探明了人类复制体指导一个专用的前导链引物酶用于叉重新启动。该研究于2026年11月11日发表于国际一流学术期刊《自然》杂志上。
前导链合成的中断会损害并停滞复制叉，因为前导链聚合酶Pol ε进行的DNA合成对于复制性CMG（CDC45–MCM–GINS）解旋酶以最佳效率解旋模板至关重要。未能有效重启和/或保护停滞的复制叉是基因组不稳定的主要来源。停滞的复制叉可通过多种机制重启，包括在障碍下游重新引发。在人类细胞中，引物酶–聚合酶PRIMPOL在复制应激期间促进复制叉推进，但其活性如何被复制体协调仍未解决。在此，研究人员利用纯化的人类蛋白重构复制叉停滞和重启，表明CMG解旋酶引导PRIMPOL以实现高效的复制叉重启。出乎意料的是，PRIMPOL与复制蛋白A之间的相互作用在该系统中对复制叉重启并非关键。研究人员表明，PRIMPOL直接结合CMG，冷冻电镜结构阐明了这种结合如何将PRIMPOL特异性靶向前导链引物合成，以最小化复制后间隙的大小。消除CMG–PRIMPOL相互作用会消除体外复制叉重启以及人类细胞中PRIMPOL依赖性的DNA损伤耐受。该工作确立了PRIMPOL作为人类复制体中一个专用于前导链引物合成的整合组分。
附：英文原文
Title: Human replisomes direct a dedicated leading-strand primase for fork restart
Author: Polo Rivera, Cristian, Roske, Johann J., Hands, Emma L., Fassetta, Federico, Sale, Julian E., Yeeles, Joseph T. P.
Issue&Volume: 2026-11-11
Abstract: Disruptions to leading-strand synthesis impair and stall replication forks because DNA synthesis by the leading-strand polymerase, Pol ε, is essential for optimal template unwinding by the replicative CMG (CDC45–MCM–GINS) helicase1,2. Failure to efficiently restart and/or protect stalled replication forks is a major source of genomic instability3,4,5,6. Stalled forks can be restarted by a variety of mechanisms, including repriming downstream of the impediment4. In human cells, the primase–polymerase PRIMPOL promotes fork progression during replication stress7,8,9,10, but how its activity is coordinated by the replisome is unresolved. Here, by reconstituting replication fork stalling and restart with purified human proteins, we show that the CMG helicase directs PRIMPOL for efficient replication fork restart. Unexpectedly, the interaction between PRIMPOL and replication protein A9,11 is not critical for fork restart in this system. We show that PRIMPOL binds directly to CMG, and a cryo-electron microscopy structure illustrates how this targets PRIMPOL specifically for leading-strand priming to minimize the size of post-replicative gaps. Ablating the CMG–PRIMPOL interaction abolishes fork restart in vitro and PRIMPOL-dependent DNA damage tolerance in human cells. Our work establishes PRIMPOL as an integrated component of the human replisome dedicated to leading-strand priming.
DOI: 10.1038/s41586-026-11204-0
Source: https://www.nature.com/articles/s41586-026-11204-0