title: A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association.
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.
authors: †Department of Biochemistry, University of California, Riverside, California 92521, United States.
authors: Wei
authors: W
authors: Zhang
authors: ‡Department of Biology, Stanford University, Stanford, California 94305, United States.
authors: Saumya
authors: S
authors: Sankaran
authors: ‡Department of Biology, Stanford University, Stanford, California 94305, United States.
authors: Or
authors: O
authors: Gozani
authors: †Department of Biochemistry, University of California, Riverside, California 92521, United States.
authors: Jikui
authors: J
authors: Song
mesh_terms: D065817:Congenital Microtia / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008844:Micrognathism / Q000235:genetics*; D009154:Mutation; D009707:Nucleosomes / Q000378:metabolism*; D051738:Origin Recognition Complex / Q000378:metabolism*; D010329:Patella / Q000002:abnormalities*
chemical_list: D009707:Nucleosomes; C497223:ORC1 protein, human; D051738:Origin Recognition Complex; D004247:DNA