迈尔-戈林综合征突变会损害ORC1与核小体的结合。
A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association.
作者信息
Zhang Wei, Sankaran Saumya, Gozani Or, Song Jikui
机构信息
†Department of Biochemistry, University of California, Riverside, California 92521, United States.
‡Department of Biology, Stanford University, Stanford, California 94305, United States.
出版信息
ACS Chem Biol. 2015 May 15;10(5):1176-80. doi: 10.1021/cb5009684. Epub 2015 Feb 24.
Abstract
Recent studies have identified several genetic mutations within the BAH domain of human Origin Recognition Complex subunit 1 (hORC1BAH), including the R105Q mutation, implicated in Meier-Gorlin Syndrome (MGS). However, the pathological role of the hORC1 R105Q mutation remains unclear. In this study, we have investigated the interactions of the hORC1BAH domain with histone H4K20me2, DNA, and the nucleosome core particle labeled with H4Kc20me2, a chemical analog of H4K20me2. Our study revealed a nucleosomal DNA binding site for hORC1BAH. The R105Q mutation reduces the hORC1BAH-DNA binding affinity, leading to impaired hORC1BAH-nucleosome interaction, which likely influences DNA replication initiation and MGS pathogenesis. This study provides an etiologic link between the hORC1 R105Q mutation and MGS.
摘要
最近的研究已经在人类复制起始识别复合物亚基1（hORC1BAH）的BAH结构域内鉴定出几种基因突变，包括与迈尔-戈林综合征（MGS）相关的R105Q突变。然而，hORC1 R105Q突变的病理作用仍不清楚。在本研究中，我们研究了hORC1BAH结构域与组蛋白H4K20me2、DNA以及用H4Kc20me2（H4K20me2的化学类似物）标记的核小体核心颗粒之间的相互作用。我们的研究揭示了hORC1BAH的一个核小体DNA结合位点。R105Q突变降低了hORC1BAH与DNA的结合亲和力，导致hORC1BAH与核小体的相互作用受损，这可能影响DNA复制起始和MGS发病机制。本研究提供了hORC1 R105Q突变与MGS之间的病因学联系。
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