A novel p53-Cdc7 link induced by genotoxic stress.
A novel p53-Cdc7 link induced by genotoxic stress.
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基因毒性应激诱导的新型 p53-Cdc7 连接。
DOI：
10.1080/15384101.2017.1304746
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Masai H
中科院分区：
文献类型：
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作者：
Masai H
保守的Cdc 7激酶调节各种染色体事件。其中，在起点处调节DNA复制的起始是Cdc 7最保守和重要的功能。Cdc 7磷酸化前复制复合物中的Mcm亚基，这触发其与Sld 3-Cdc 45的缔合以促进CMG解旋酶的形成。Cdc 7还涉及对复制/遗传毒性应激的细胞应答。在酵母中，Dbf 4，激活亚基，是复制检查点的靶标。Rad 53检查点激酶对Dbf 4的磷酸化是响应于复制应激而抑制复制起始的机制的一部分。1，2另一方面，Cdc 7在检查点激活中的作用也已显示。其中，Mrc 1/Claspin是Cdc 7激酶在复制检查点激活中的潜在靶点。在最近一期的《细胞周期》杂志上，Tudzarova和她的同事报道了一种涉及Cdc 7的新型遗传毒性应激检查点。5作者发现，在IMR 90成纤维细胞从血清饥饿中释放时，Cdc 7蛋白水平响应于遗传毒性应激（辐射或多柔比星）而显著降低。值得注意的是，这种减少取决于p53功能。此外，转录和转录后（蛋白质稳定性）途径都对Cdc 7表达的p53依赖性抑制起作用。前者由p53-miR-192/215-Cdc 7介导，而后者由p53-Fbxw 7 b（泛素连接酶）-p53途径介导。这些途径的激活抑制进入S期的DNA损伤的存在下。
The conserved Cdc7 kinase regulates various chromosome events. Among them, regulation of initiation of DNA replication at origins is the most conserved and important function of Cdc7. Cdc7 phosphorylates subunits of Mcm in the pre-Replicative Complex, which triggers its association with Sld3-Cdc45 to facilitate formation of the CMG helicase. Cdc7 has also been implicated in cellular responses to replication/genotoxic stress. In yeast, Dbf4, the activation subunit, is a target of replication checkpoint. Phosphorylation of Dbf4 by Rad53 checkpoint kinase is a part of mechanism that inhibits replication initiation in response to replication stress. 1, 2 On the other hand, roles of Cdc7 in checkpoint activation also have been shown. Among them, Mrc1/Claspin is a potential target of Cdc7 kinase in replication checkpoint activation. 3, 4In a recent issue of Cell Cycle, Tudzarova and her colleagues reported a novel genotoxic stress checkpoint that involves Cdc7. 5 Authors found that Cdc7 protein level is significantly reduced in response to genotoxic stress (irradiation or Doxorubicin) in release from serum starvation of IMR90 fibroblast cells. Notably, this reduction depends on p53 function. Furthermore, both transcriptional and post-transcriptional (protein stability) pathways operate for the p53-dependent inhibition of Cdc7 expression. The former is mediated by the p53-miR-192/215-Cdc7, whereas the latter by p53-Fbxw7b (ubiquitin ligase)-p53 pathway. Activation of these pathways inhibited the entry into S phase in the presence of DNA damages.