Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress.
Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress.
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DOI：
10.1038/nature25507
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发表时间：
2018-03-01
期刊：
影响因子：
64.8
通讯作者：
Halazonetis TD
中科院分区：
文献类型：
--
作者：
Macheret M;Halazonetis TD
癌基因诱导的DNA复制应激对癌症中存在的基因组不稳定性有重要贡献。然而，阐明癌基因如何去调节DNA复制一直受到阻碍的困难，在映射复制起始位点的人类基因组。在这项研究中，使用一种敏感的检测方法来监测早期S期的新生DNA合成，我们确定了癌基因CCNE1或MYC诱导前后细胞中数千个复制起始位点。值得注意的是，这两种癌基因都诱导了一组新的DNA复制起点，这些复制起点定位在高度转录的基因中。这些异位起源通常在G1期被转录抑制，但在所有基因区域被转录之前过早进入S期，允许在具有激活的癌基因的细胞中基因内的起源被激发。由于复制和转录之间的冲突，来自癌基因诱导的起源的分叉容易崩溃，并且在我们的实验系统和大量人类癌症中与DNA双链断裂形成和染色体重排断点相关。因此，由过早进入S期引起的基因内起点的发射代表了与人类癌症中基因组不稳定性相关的癌基因诱导的DNA复制应激的机制。
Oncogene-induced DNA replication stress contributes critically to the genomic instability present in cancer. However, elucidating how oncogenes deregulate DNA replication has been impeded by the difficulty in mapping replication initiation sites on the human genome. In this study, 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 or 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, prior to all genic regions having 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-strand 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.
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