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

Article

关键词: COPY-NUMBER ALTERATION;    INDUCED SENESCENCE;    HUMAN-CELLS;    CYCLIN-E;    TRANSCRIPTION UNITS;    CANCER DEVELOPMENT;    FRAGILE SITES;    GENOME;    INITIATION;    INSTABILITY;   

DOI  :  10.1038/nature25507

来源: SCIE

【 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.

【 授权许可】

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