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首页> 外文期刊>Cell cycle >Network architecture of signaling from uncoupled helicase-polymerase to cell cycle checkpoints and trans-lesion DNA synthesis.
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Network architecture of signaling from uncoupled helicase-polymerase to cell cycle checkpoints and trans-lesion DNA synthesis.

机译：从解偶联解旋酶-聚合酶到细胞周期检查点和跨病变DNA合成的信号传递的网络体系结构。

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When replication is blocked by a template lesion or polymerase inhibitor while helicase continues unwinding the DNA, single stranded DNA (ssDNA) accumulates and becomes coated with RPA, which then initiates signals via PCNA mono-ubiquitination to activate trans-lesion polymerases and via ATR and Chk1 to inhibit Cdk2-dependent cell cycle progression. The signals are conveyed by way of a complex network of molecular interactions. To clarify those complexities, we have constructed a molecular interaction map (MIM) using a novel hierarchical assembly procedure. Molecules were arranged on the map in hierarchical levels according to interaction step distance from the DNA region of stalled replication. The hierarchical MIM allows us to disentangle the network's interlocking pathways and loops and to suggest functionally significant features of network architecture. The MIM shows how parallel pathways and multiple feedback loops can provide failsafe and robust switch-like responses to replication stress. Within the central level of hierarchy ATR and Claspin together appear to function as a nexus that conveys signals from many sources to many destinations. We noted a division of labor between those two molecules, separating enzymatic and structural roles. In addition, the network architecture disclosed by the hierarchical map, suggested a speculative model for how molecular crowding and the granular localization of network components in the cell nucleus can facilitate function.
机译：当模板损伤或聚合酶抑制剂阻止复制，而解旋酶继续解旋DNA时，单链DNA（ssDNA）积累并被RPA覆盖，然后通过PCNA单泛素化来启动信号，从而激活跨病变的聚合酶以及ATR和Chk1抑制Cdk2依赖的细胞周期进程。信号通过复杂的分子相互作用网络进行传递。为了阐明这些复杂性，我们使用新颖的层次组装程序构建了分子相互作用图（MIM）。根据与停滞复制的DNA区域之间的相互作用步距，将分子按层次层次排列在地图上。分层MIM使我们能够解开网络的互锁路径和环路，并提出网络体系结构在功能上的重要功能。 MIM显示了并行路径和多个反馈环路如何能够提供对复制压力的故障安全和鲁棒的类似开关的响应。在等级体系的中央层次上，ATR和Claspin一起似乎充当了一个将信号从许多来源传递到许多目的地的纽带。我们注意到这两个分子之间的分工，将酶的作用和结构的作用分开了。另外，由分层图公开的网络体系结构提出了一种推测模型，该模型用于分子拥挤和细胞核中网络组件的颗粒定位如何促进功能。

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