Identification of a Heteromeric Complex That Promotes DNA Replication Origin Firing in Human Cells
Identification of a Heteromeric Complex That Promotes DNA Replication Origin Firing in Human Cells
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DOI：
10.1126/science.1237448
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发表时间：
2013-05-24
期刊：
影响因子：
56.9
通讯作者：
Diffley, John F. X.
中科院分区：
文献类型：
--
作者：
Boos, Dominik;Yekezare, Mona;Diffley, John F. X.
Treslin/TICRR(TopBP1-相互作用，复制刺激蛋白/TopBP1-相互作用，检查点和复制调节因子)是酵母SLD3蛋白的人类同源基因，是一种重要的DNA复制因子，受细胞周期蛋白依赖的蛋白和DNA损伤检查点的调节。我们发现MDM 2结合蛋白(MTBP)是一个在整个细胞周期中与Treslin/TICRR相互作用的因子。我们证明了通过小干扰RNA耗尽MTBP通过阻止CMG(CDC45-MCM-GINS)全面体酶在起始点火过程中的组装来抑制DNA复制。尽管MTBP与P53抑癌基因的功能有关，但我们发现无论细胞的P53状态如何，MTBP都是DNA复制所必需的。我们认为，MTBP与Treslin/TICRR共同作用，整合细胞周期和DNA损伤反应通路的信号，控制DNA复制在人类细胞中的启动。
Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holoheticase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.