近日，英国弗朗西斯克里克研究所Alessandro Costa及其研究组的论文发现了预启动复合体的结构解释了CMGE的生物合成。相关论文于2026年6月17日发表在《自然》杂志上。

为了了解CMGE的生物发生，该课题组研究人员用纯化的酵母蛋白重组了起始前复合物。低温电子显微镜结构显示了在组装两个对称CMGE时捕获的一组发射因子。研究组展示了如何逐步复杂的形成重塑MCM，以准备DNA打开，研究组解释了ATP如何促进燃烧因子的喷射和CMGE的成熟。该团队发现，虽然Sld2如预期的那样促进了GINS向MCM的招募，但它也有助于CMGE二聚体的有效分离，并且对于从MCM中弹出滞后链至关重要。这些发现直接影响了他们对后生动物Sld2同源基因RECQL4的理解，并指出了一种在真核生物中保守的复制叉建立机制。

据悉，当细胞进入S期时，通过激酶调控的三种激活因子(Cdc45、GINS和Polε)转化为双DNA负载的双六聚体的小染色体维持（MCM） ATP酶。这些蛋白质一起形成了两个CMGE解旋酶，当它们分离时，它们会建立不同的复制叉。

附：英文原文

Title: Structure of the pre-initiation complex explains CMGE biogenesis

Author: Phringer, Thomas, Canal, Berta, Palm, Giacomo, Butryn, Agata, Couves, Emma C., Willhoft, Oliver, Lewis, Jacob S., Diffley, John F. X., Costa, Alessandro

Issue&Volume: 2026-06-17

Abstract: When cells enter S phase, bidirectional DNA replication is initiated through the kinase-regulated recruitment of three activators (Cdc45, GINS and Polε) to a duplex-DNA-loaded double hexamer of minichromosome maintenance (MCM) ATPases. Together, these proteins form two CMGE helicases that establish divergent replication forks as they become separated1. Here, to gain an understanding of CMGE biogenesis, we reconstituted the pre-initiation complex with purified yeast proteins. The cryo-electron-microscopy structure shows a set of firing factors caught in the act of assembling two symmetrical CMGEs. We show how stepwise complex formation reshapes MCM in preparation for DNA opening, and we explain how ATP promotes firing-factor ejection and CMGE maturation. We find that although Sld2 facilitates the recruitment of GINS to MCM, as expected, it also aids the efficient separation of the CMGE dimer, and is essential for the ejection of the lagging strand from MCM. These findings have direct implications for our understanding of the metazoan Sld2 orthologue, RECQL4, and point to a replication-fork establishment mechanism that is conserved across eukaryotes.

DOI: 10.1038/s41586-026-10657-7

Source: https://www.nature.com/articles/s41586-026-10657-7

期刊信息

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