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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation
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Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation

机译：人类Claspin与BRCA1共同作用，以正向和负向调节细胞增殖

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摘要

Claspin is a homolog of Mrc1, a checkpoint protein required for the DNA replication checkpoint in yeast. In Xenopus, phosphorylated Claspin binds to xChk1 and regulates xChk1 activation in response to replication stress. In this study, we have shown that the human homolog of Claspin is required for resistance to multiple forms of genotoxic stress including UV, IR, and hydroxyurea. Phosphorylation of Claspin was found to depend on the ataxia telangiectasia mutated-Rad3 related (ATR) pathway. DNA damage induces the formation of a complex between Claspin and BRCA1, a second regulator of Chk1 activation. Claspin was found to control BRCA1 phosphorylation on serine 1524, a site whose phosphorylation is controlled by the ATR pathway. These results are consistent with a model in which ATR regulates Claspin phosphorylation in response to DNA damage and replication stress resulting in recruitment and phosphorylation of BRCA1. BRCA1 and Claspin then function to activate the tumor suppressor Chk1. Unexpectedly, we found that Claspin has a second, positive role in control of the cell cycle as Claspin overexpression increased cell proliferation. These results suggest that Claspin has properties of both a tumor suppressor and an oncogene.
机译：Claspin是Mrc1的同源物，Mrc1是酵母中DNA复制检查点所需的检查点蛋白。在非洲爪蟾中，磷酸化的Claspin与xChk1结合并调节xChk1的激活以响应复制压力。在这项研究中，我们已经表明，人类对Claspin的同源性是抵抗多种形式的遗传毒性胁迫（包括UV，IR和羟基脲）所必需的。发现Claspin的磷酸化取决于共济失调毛细血管扩张突变-Rad3相关（ATR）途径。 DNA损伤诱导Claspin和BRCA1（Chk1活化的第二个调节因子）之间形成复合物。发现Claspin控制丝氨酸1524上的BRCA1磷酸化，该位点的磷酸化受ATR途径控制。这些结果与一个模型相符，在该模型中，ATR响应DNA损伤和复制应激（导致BRCA1募集和磷酸化）来调节Claspin磷酸化。然后，BRCA1和Claspin起作用以激活肿瘤抑制因子Chk1。出乎意料的是，我们发现Claspin在细胞周期控制中具有第二种积极作用，因为Claspin过表达会增加细胞增殖。这些结果表明，Claspin具有肿瘤抑制物和癌基因的性质。

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