DONSON is required for CMG helicase assembly in the mammalian cell cycle.
DONSON is required for CMG helicase assembly in the mammalian cell cycle.
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在哺乳动物细胞周期中，DONSON是CMG解旋酶组装所必需的。
DOI：
10.15252/embr.202357677
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发表时间：
2023-11-06
期刊：
影响因子：
7.7
通讯作者：
Labib, Karim P. M.
中科院分区：
文献类型：
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作者：
Evrin, Cecile;Alvarez, Vanesa;Ainsworth, Johanna;Fujisawa, Ryo;Alabert, Constance;Labib, Karim P. M.
DONSON是13个基因突变的原始小头侏儒症形式之一，称为Meier-Gorlin综合征。其他12个编码CDC 45-MCM-GINS解旋酶的组分，真核复制体在其周围形成，或者是DNA复制起始期间解旋酶组装所需的因子。DONSON在CDC 45-MCM-GINS组装中的作用是意料之外的，因为DNA复制起始可以在体外用来自芽殖酵母的纯化蛋白质重建，而芽殖酵母缺乏DONSON。使用小鼠胚胎干细胞作为哺乳动物解旋酶的模型，我们表明DONSON在S期直接但短暂地结合到CDC 45-MCM-GINS，并且对于染色体复制是必需的。DONSON的快速消耗导致S期细胞中CDC 45-MCM-GINS解旋酶的消失，我们的数据表明，DONSON在G1期期间将MCM 2 - 7解旋酶核心加载到染色质上，但在S期期间对CDC 45-MCM-GINS组装至关重要。这些数据将DONSON确定为我们对哺乳动物染色体复制的理解中缺失的一环，并为人类DONSON突变与Meier-Gorlin综合征相关提供了分子解释。DONSON是哺乳动物细胞中CMG解旋酶组装所必需的。这解释了为什么人类DONSON中的亚晶突变会导致Meier-Gorlin综合征，这与CMG解旋酶组装或功能缺陷有关。
DONSON is one of 13 genes mutated in a form of primordial microcephalic dwarfism known as Meier‐Gorlin syndrome. The other 12 encode components of the CDC45‐MCM‐GINS helicase, around which the eukaryotic replisome forms, or are factors required for helicase assembly during DNA replication initiation. A role for DONSON in CDC45‐MCM‐GINS assembly was unanticipated, since DNA replication initiation can be reconstituted in vitro with purified proteins from budding yeast, which lacks DONSON. Using mouse embryonic stem cells as a model for the mammalian helicase, we show that DONSON binds directly but transiently to CDC45‐MCM‐GINS during S‐phase and is essential for chromosome duplication. Rapid depletion of DONSON leads to the disappearance of the CDC45‐MCM‐GINS helicase from S‐phase cells and our data indicate that DONSON is dispensable for loading of the MCM2‐7 helicase core onto chromatin during G1‐phase, but instead is essential for CDC45‐MCM‐GINS assembly during S‐phase. These data identify DONSON as a missing link in our understanding of mammalian chromosome duplication and provide a molecular explanation for why mutations in human DONSON are associated with Meier‐Gorlin syndrome. DONSON is required for assembly of the CMG helicase in mammalian cells. This explains why hypomorphic mutations in human DONSON cause Meier‐Gorlin Syndrome, which is associated with defects in CMG helicase assembly or function.
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