首页> 外文期刊>Nature >Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress
【24h】

Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress

机译:G1期短导致的基因内起源是致癌基因诱导的DNA复制压​​力的基础

获取原文
获取原文并翻译 | 示例
       

摘要

Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer(1-4). However, elucidating how oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the oncogenes CCNE1 and MYC. Remarkably, both oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
机译:癌基因诱导的DNA复制应激是导致癌症中基因组不稳定的关键因素(1-4)。但是,由于难以在人类基因组上绘制复制起始位点,因此难以阐明致癌基因如何解除DNA复制的作用。在这里,我们使用一种敏感的检测方法来监测S期早期新生DNA的合成,我们在致癌基因CCNE1和MYC诱导之前和之后鉴定了细胞中成千上万的复制起始位点。值得注意的是,两个癌基因均诱导了一组新的DNA复制起点的映射,这些起点在高度转录的基因中定位。这些异位起源通常在G1期间被转录抑制,但是在转录所有基因区域之前,早熟进入S期,可以激活具有癌基因的细胞中的起源。由于复制和转录之间的冲突,致癌基因诱导的起源的叉容易倒塌,并且在我们的实验系统和大量人类癌症中均与DNA双链断裂形成和染色体重排断裂点有关。因此,由S期过早进入引起的基因内起源的激发代表了癌基因诱导的DNA复制应激的机制,该机制与人类癌症的基因组不稳定有关。

著录项

  • 来源
    《Nature》 |2018年第7694期|112-116|共5页
  • 作者单位

    Univ Geneva, Dept Mol Biol, CH-1205 Geneva, Switzerland;

    Univ Geneva, Dept Mol Biol, CH-1205 Geneva, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);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

  • 入库时间 2022-08-18 02:51:27

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号