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首页> 外文期刊>Molecular cell >Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress
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Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress

机译：Rad17磷酸化对于claspin募集和响应复制压力的Chk1激活是必需的

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摘要

The ATR-mediated checkpoint is not only critical for responding to genotoxic stress but also essential for cell proliferation. The RFC-related checkpoint protein Rad17, a phosphorylation substrate of ATR, is critical for ATR-mediated checkpoint signaling and cell survival. Here, we show that phosphorylation of Rad17 by ATR is important for genomic stability and restraint of S phase but is not essential for cell survival. The phosphomutant Rad17AA exhibits distinct defects in hydroxyurea- (HU) and ultraviolet-(UV) induced Chk1 activation, indicating that separate Rad17 functions are required differently in response to different types of replication interference. Although cells expressing Rad17AA can initiate Chk1 phosphorylation after HU treatment, they fail to sustain Chk1 phosphorylation after withdrawal of HU and are profoundly sensitive to HU. Importantly, we found that phosphorylated Rad17 interacts with Claspin and regulates its phosphorylation. These findings reveal a phosphorylation-dependent function of Rad17 in an ATR-Rad17-Claspin-Chk1 -signaling cascade that responds to specific replication stress.
机译：ATR介导的检查点不仅对应对遗传毒性胁迫至关重要，而且对细胞增殖也至关重要。 RFC相关检查点蛋白Rad17（ATR的磷酸化底物）对于ATR介导的检查点信号和细胞存活至关重要。在这里，我们表明，ATR对Rad17的磷酸化对于基因组稳定性和S期抑制很重要，但对细胞存活不是必需的。磷酸突变体Rad17AA在羟基脲（HU）和紫外线（UV）诱导的Chk1活化中表现出明显的缺陷，表明响应不同类型的复制干扰，需要不同的单独Rad17功能。尽管表达Rad17AA的细胞可以在HU处理后启动Chk1磷酸化，但它们在HU退出后仍无法维持Chk1磷酸化，并且对HU极为敏感。重要的是，我们发现磷酸化的Rad17与Claspin相互作用并调节其磷酸化。这些发现揭示了ATR-Rad17-Claspin-Chk1信号级联反应中Rad17的磷酸化依赖性功能，该信号响应特定的复制应激。

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