生物信息学
生物
解旋酶
蛋白质亚单位
DNA复制
细胞生物学
染色质
微小染色体维持
复制的起源
计算生物学
遗传学
DNA
基因
核糖核酸
作者
Yang Lim,Lukas Tamayo-Orrego,E. Schmid,Žygimantė Tarnauskaitė,Olga V. Kochenova,Rhian Gruar,Sachiko Muramatsu,Luke D. Lynch,Aitana Verdu Schlie,Paula L. Carroll,Gheorghe Chistol,Martin A.M. Reijns,Masato T. Kanemaki,Andrew P. Jackson,Johannes C. Walter
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2023-09-22
卷期号:381 (6664)
被引量:24
标识
DOI:10.1126/science.adi3448
摘要
CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit “pre-loading complex” (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates. Using AlphaFold to screen for protein-protein interactions followed by experimental validation, we show that DONSON scaffolds a vertebrate pre-LC containing GINS, TOPBP1, and DNA pol ε. Our evidence suggests that DONSON docks the pre-LC onto MCM2-7, delivering GINS to its binding site in CMG. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. These results unify our understanding of eukaryotic replication initiation, implicate defective CMG assembly in microcephalic dwarfism, and illustrate how in silico protein-protein interaction screening accelerates mechanistic discovery.
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