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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functional genomic screens identify CINP as a genome maintenance protein
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Functional genomic screens identify CINP as a genome maintenance protein

机译：功能基因组筛选将CINP鉴定为基因组维持蛋白

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摘要

The DNA damage response (DDR) has a critical role in maintaining genome integrity and serves as a barrier to tumorigenesis by promoting cell-cycle arrest, DNA repair, and apoptosis. The DDR is activated not only by genotoxic agents that induce DNA damage, but also during aberrant cell-division cycles caused by activated oncogenes and inactivated tumor suppressors. Here we use RNAi and cDNA overexpression screens in human cells to identify genes that, when deregulated, lead to activation of the DDR. The RNAi screen identified 73 genes that, when silenced in at least two cell types, cause DDR activation. Silencing several of these genes also caused an increased frequency of micronuclei, a marker of genetically unstable cells. The cDNA screen identified 97 genes that when overexpressed induce DDR activation in the absence of any exogenous genotoxic agent, with an overrepresentation of genes linked to cancer. Secondary RNAi screens identified CDK2-interacting protein (CINP) as a cell-cycle checkpoint protein. CINP interacts with ATR-interacting protein and regulates ATR-dependent signaling, resistance to replication stress, and G2 checkpoint integrity.
机译：DNA损伤反应（DDR）在维持基因组完整性方面具有关键作用，并通过促进细胞周期停滞，DNA修复和凋亡而成为肿瘤发生的障碍。 DDR不仅被引起DNA损伤的遗传毒性剂激活，而且在激活的癌基因和灭活的肿瘤抑制物引起的异常细胞分裂周期中被激活。在这里，我们使用人类细胞中的RNAi和cDNA过表达筛选来鉴定基因，这些基因被解除调节后会导致DDR激活。 RNAi筛选确定了73种基因，这些基因在至少两种细胞类型中沉默后会导致DDR激活。使其中几个基因沉默也会导致微核（遗传不稳定细胞的标志物）频率增加。 cDNA筛选确定了97个基因，这些基因在不存在任何外源遗传毒性剂的情况下过度表达时会诱导DDR激活，而与癌症相关的基因则过度表达。二级RNAi筛选将CDK2相互作用蛋白（CINP）鉴定为细胞周期检查点蛋白。 CINP与ATR相互作用蛋白相互作用，并调节ATR依赖性信号传导，抗复制压力和G2检查点完整性。

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  • 作者

    Courtney A. Lovejoy; Xin Xu; Carol E. Bansbach; Gloria G. Glick; Runxiang Zhao; Fei Ye; Bianca M. Sirbu; Laura C. Titus; Yu Shyr; David Cortez;

  • 作者单位

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    ataxia telangiectasia-mutated and Rad3-related; ATR-interacting protein; checkpoint; DNA damage response;

    机译：共济失调毛细血管扩张突变和Rad3相关;ATR相互作用蛋白;检查站DNA损伤反应;

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