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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >DNA damage and elF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs
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DNA damage and elF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs

机译：乳腺癌细胞中的DNA损伤和elF4G1重新编程翻译以求生存和DNA修复mRNA

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摘要

The cellular response to DNA damage is mediated through multiple pathways that regulate and coordinate DNA repair, cell cycle arrest, and cell death. We show that the DNA damage response (DDR) induced by ionizing radiation (IR) is coordinated in breast cancer cells by selective mRNA translation mediated by high levels of translation initiation factor elF4G1 (eukaryotic initiation factor 4γ1). Increased expression of elF4G1, common in breast cancers, was found to selectively increase translation of mRNAs involved in cell survival and the DDR, preventing autophagy and apoptosis [Survivin, hypoxia inducible factor 1α (HIF1α), X-linked inhibitor of apoptosis (XIAP)], promoting cell cycle arrest [growth arrest and DNA damage protein 45a (GADD45a), protein 53 (p53), ATR-interacting protein (ATRIP), Check point kinase 1 (Chk1)] and DNA repair [p53 binding protein 1 (S3BP1), breast cancer associated proteins 1, 2 (BRCA1/2), Poly-ADP ribose polymerase (PARP), replication factor c2-5 (Ric2-S), ataxia telangiectasia mutated gene 1 (ATM), meiotic recombination protein 11 (MRE-11), and others]. Reduced expression of elF4G1, but not its homolog elF4G2, greatly sensitizes cells to DNA damage by IR, induces cell death by both apoptosis and autophagy, and significantly delays resolution of DNA damage foci with little reduction of overall protein synthesis. Although some mRNAs selectively translated by higher levels of elF4G1 were found to use internal ribosome entry site (IRES)-mediated alternate translation, most do not. The latter group shows significantly reduced dependence on elF4E for translation, facilitated by an enhanced requirement for elF4G1. Increased expression of elF4G1 therefore promotes specialized translation of survival, growth arrest, and DDR mRNAs that are important in cell survival and DNA repair following genotoxic DNA damage.
机译：细胞对DNA损伤的反应是通过调节和协调DNA修复，细胞周期停滞和细胞死亡的多种途径介导的。我们显示，通过高水平翻译起始因子eIF4G1（真核起始因子4γ1）介导的选择性mRNA翻译，在乳腺癌细胞中由电离辐射（IR）诱导的DNA损伤反应（DDR）得到协调。发现增加在乳腺癌中常见的elF4G1的表达可以选择性增加参与细胞存活和DDR的mRNA的翻译，从而防止自噬和凋亡[Survivin，缺氧诱导因子1α（HIF1α），X连锁凋亡抑制剂（XIAP） ]，促进细胞周期阻滞[生长阻滞和DNA损伤蛋白45a（GADD45a），蛋白53（p53），ATR相互作用蛋白（ATRIP），检查点激酶1（Chk1）]和DNA修复[p53结合蛋白1（S3BP1） ），乳腺癌相关蛋白1、2（BRCA1 / 2），聚ADP核糖聚合酶（PARP），复制因子c2-5（Ric2-S），共济失调毛细血管扩张突变基因1（ATM），减数分裂重组蛋白11（MRE） -11），以及其他]。降低的elF4G1表达，而不是其同源物elF4G2，使细胞对IR引起的DNA损伤非常敏感，通过凋亡和自噬诱导细胞死亡，并显着延迟了DNA损伤灶的分离，而总蛋白质合成几乎没有减少。尽管发现通过较高水平的elF4G1选择性翻译的某些mRNA使用内部核糖体进入位点（IRES）介导的交替翻译，但大多数不使用。后一组显示对elF4E的翻译依赖性大大降低，这是由于对elF4G1的需求增加所致。因此，eIF4G1表达的增加促进了生存，生长停滞和DDR mRNA的特异翻译，这些基因对遗传毒性DNA损伤后的细胞存活和DNA修复很重要。

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  • 作者

    Michelle Badura; Steve Braunstein; Jiri Zavadil; Robert J. Schneider;

  • 作者单位

    Department of Microbiology, New York University School of Medicine, New York, NY 10016,Department of Radiation Oncology, University of California, San Francisco, CA 94127;

    Department of Microbiology, New York University School of Medicine, New York, NY 10016,School of Medicine, Stanford University, Palo Alto, CA 94305;

    NYU Cancer Institute, New York University School of Medicine, New York, NY 10016;

    Department of Microbiology, New York University School of Medicine, New York, NY 10016,NYU Cancer Institute, New York University School of Medicine, New York, NY 10016,Department of Radiation Oncology, New York University School of Medicine, New York, NY 10016;

  • 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

    translational control; elF;

    机译：翻译控制;精灵;

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