英国邓迪大学Karim P. M. Labib、Ye Hong以及英国MRC分子生物学实验室Joseph T. P. Yeeles研究组发现，在秀丽隐杆线虫DNA复制起始过程中，DNSN -1招募GINS用于CMG解旋酶组装。该研究于2023年8月17日发表于国际一流学术期刊《科学》杂志上。

他们发现秀丽隐杆线虫的DNSN -1，人类DONSON的同源物，在与mus101 /TOPBP1复合物的解旋酶组装中起作用。DNSN -1需要将GINS复合物招募到染色质上，冷冻电镜结构表明，DNSN -1通过直接将DNSN -1与GINS和MCM-3结合在MCM-2-7解旋酶马达上，将GINS定位在MCM-2-7解旋酶马达上，他们发现这些接口对起始和生存至关重要。

这些发现确定了DNSN -1是我们对DNA复制起始的理解中缺失的一环，表明起始缺陷是由DONSON突变引起的人类疾病综合征的基础。

据悉，CDC45-MCM-GINS解旋酶的组装是真核生物DNA复制起始的关键调控步骤。到目前为止，尚不清楚后生动物是否需要酵母中不存在的其他因素。

附：英文原文

Title: DNSN-1 recruits GINS for CMG helicase assembly during DNA replication initiation in Caenorhabditis elegans

Author: Yisui Xia, Remi Sonneville, Michael Jenkyn-Bedford, Liqin Ji, Constance Alabert, Ye Hong, Joseph T. P. Yeeles, Karim P. M. Labib

Issue&Volume: 2023-08-17

Abstract: Assembly of the CDC45-MCM-GINS helicase is the key regulated step during eukaryotic DNA replication initiation. Until now, it was unclear whether metazoa require additional factors not present in yeast. Here, we show that Caenorhabditis elegans DNSN-1, the ortholog of human DONSON, functions during helicase assembly in a complex with MUS-101/TOPBP1. DNSN-1 is required to recruit the GINS complex to chromatin, and a cryo-electron microscopy structure indicates that DNSN-1 positions GINS on the MCM-2-7 helicase motor, by direct binding of DNSN-1 to GINS and MCM-3, using interfaces that we show are important for initiation and essential for viability. These findings identify DNSN-1 as a missing link in our understanding of DNA replication initiation, suggesting that initiation defects underlie the human disease syndrome resulting from DONSON mutations.

DOI: adi4932

Source: https://www.science.org/doi/full/10.1126/science.adi4932