Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. 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.

中文翻译：

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短 G1 期导致的基因内起源是癌基因诱导的 DNA 复制应激的基础

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影响。然而，由于难以绘制人类基因组上的复制起始位点，阐明癌基因如何解除 DNA 复制的调控受到了阻碍。在这里，我们使用灵敏的检测方法监测早期 S 期的新生 DNA 合成，在癌基因 CCNE1 和 MYC 诱导前后确定了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 复制起点的激发，这些复制起点映射在高度转录的基因内。这些异位起源通常在 G1 期间被转录抑制，但在所有基因区域转录之前提前进入 S 期，允许在具有激活癌基因的细胞中激发基因内的起源。由于复制和转录之间的冲突，来自癌基因诱导起源的分叉很容易崩溃，并且在我们的实验系统和大量人类癌症中都与DNA双链断裂形成和染色体重排断点相关。因此，过早进入S期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，其与人类癌症中的基因组不稳定性相关。