DONSON facilitates Cdc45 and GINS chromatin association and is essential for DNA replication initiation.
DONSON facilitates Cdc45 and GINS chromatin association and is essential for DNA replication initiation.
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DOI：
10.1093/nar/gkad694
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发表时间：
2023-10-13
影响因子：
14.9
通讯作者：
Gambus, Agnieszka
中科院分区：
文献类型：
--
作者：
Kingsley, Georgia;Skagia, Aggeliki;Passaretti, Paolo;Fernandez-Cuesta, Cyntia;Reynolds-Winczura, Alicja;Koscielniak, Kinga;Gambus, Agnieszka
忠实的细胞分裂是生命繁殖的基础，DNA复制必须受到精确调控。 DNA 复制应激是基因组不稳定的一个重要内源性来源，它不仅会导致衰老，还会导致人类神经病理学和癌症的发展。具体来说，脊椎动物细胞如何选择和激活复制起点的问题非常重要，例如，起点激发不足会导致基因组不稳定，而复制起始因子的突变会导致罕见的人类疾病迈耶-戈林综合征。起源激活机制已在酵母中得到很好的表征和重建，然而，在高等真核生物中缺乏对这一过程的同等理解。复制起点的激发由 S 期激酶（CDK 和 DDK）驱动，导致复制解旋酶激活并产生两个双向复制叉。我们从无细胞非洲爪蟾卵提取物中获得的数据表明，在复制起始过程中，DONSON 是在起始点组装活性复制解旋酶（CMG 复合物）所必需的。此前已证明 DONSON 在人类细胞和果蝇中的 DNA 复制过程中至关重要，但 DONSON 的作用机制尚不清楚。在这里，我们表明 DONSON 的存在对于复制启动至关重要，因为它是 Cdc45 和 GINS 与 Mcm2-7 复合物的关联以及解旋酶激活所必需的。为了发挥这一作用，DONSON 以 CDK 依赖性方式与起始因子 TopBP1 相互作用。继其起始作用之后，DONSON 还在 DNA 复制的延伸阶段形成复制体的一部分。最近已证明 DONSON 突变会导致迈耶-戈林综合征；因此，DONSON 的这种新颖的复制启动作用为患者中 DONSON 突变引起的表型提供了解释。
Faithful cell division is the basis for the propagation of life and DNA replication must be precisely regulated. DNA replication stress is a prominent endogenous source of genome instability that not only leads to ageing, but also neuropathology and cancer development in humans. Specifically, the issues of how vertebrate cells select and activate origins of replication are of importance as, for example, insufficient origin firing leads to genomic instability and mutations in replication initiation factors lead to the rare human disease Meier-Gorlin syndrome. The mechanism of origin activation has been well characterised and reconstituted in yeast, however, an equal understanding of this process in higher eukaryotes is lacking. The firing of replication origins is driven by S-phase kinases (CDKs and DDK) and results in the activation of the replicative helicase and generation of two bi-directional replication forks. Our data, generated from cell-free Xenopus laevis egg extracts, show that DONSON is required for assembly of the active replicative helicase (CMG complex) at origins during replication initiation. DONSON has previously been shown to be essential during DNA replication, both in human cells and in Drosophila, but the mechanism of DONSON’s action was unknown. Here we show that DONSON’s presence is essential for replication initiation as it is required for Cdc45 and GINS association with Mcm2–7 complexes and helicase activation. To fulfil this role, DONSON interacts with the initiation factor, TopBP1, in a CDK-dependent manner. Following its initiation role, DONSON also forms a part of the replisome during the elongation stage of DNA replication. Mutations in DONSON have recently been shown to lead to the Meier-Gorlin syndrome; this novel replication initiation role of DONSON therefore provides the explanation for the phenotypes caused by DONSON mutations in patients.
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