裂殖酵母中DNA复制检查点激酶Cds1激活的双阶段机制。
Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast.
作者信息
Xu Yong-jie, Davenport Matthew, Kelly Thomas J
机构信息
Program in Molecular Biology, Sloan-Kettering Institute, New York, New York 10021, USA.
出版信息
Genes Dev. 2006 Apr 15;20(8):990-1003. doi: 10.1101/gad.1406706.
Abstract
The DNA replication checkpoint is a complex signal transduction pathway, present in all eukaryotic cells, that functions to maintain genomic integrity and cell viability when DNA replication is perturbed. In Schizosaccharomyces pombe the major effector of the replication checkpoint is the protein kinase Cds1. Activation of Cds1 is known to require the upstream kinase Rad3 and the mediator Mrc1, but the biochemical mechanism of activation is not well understood. We report that the replication checkpoint is activated in two stages. In the first stage, Mrc1 recruits Cds1 to stalled replication forks by interactions between the FHA domain of Cds1 and specific phosphorylated Rad3 consensus sites in Mrc1. Cds1 is then primed for activation by Rad3-dependent phosphorylation. In the second stage, primed Cds1 molecules dimerize via phospho-specific interactions mediated by the FHA domains and are activated by autophosphorylation. This two-stage activation mechanism for the replication checkpoint allows for rapid activation with a high signal-to-noise ratio.
摘要
DNA复制检查点是一种存在于所有真核细胞中的复杂信号转导途径，当DNA复制受到干扰时，它发挥作用以维持基因组完整性和细胞活力。在粟酒裂殖酵母中，复制检查点的主要效应器是蛋白激酶Cds1。已知Cds1的激活需要上游激酶Rad3和介质Mrc1，但激活的生化机制尚不清楚。我们报告复制检查点分两个阶段被激活。在第一阶段，Mrc1通过Cds1的FHA结构域与Mrc1中特定的磷酸化Rad3共有位点之间的相互作用，将Cds1募集到停滞的复制叉处。然后，Cds1通过Rad3依赖性磷酸化被启动激活。在第二阶段，被启动的Cds1分子通过FHA结构域介导的磷酸特异性相互作用二聚化，并通过自磷酸化被激活。这种复制检查点的两阶段激活机制允许以高信噪比进行快速激活。
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