Abstract
Oncogenes induce premature S phase, resulting in replication–transcription conflicts and replication stress.
Major finding: Oncogenes induce premature S phase, resulting in replication–transcription conflicts and replication stress.
Mechanism: CCNE1- or MYC-induced origins are prone to fork collapse and DNA double-strand breaks.
Impact: Firing of intragenic origins due to premature S phase may underlie replication stress in cancer.
Oncogene-induced DNA replication stress promotes genomic instability in cancer, but the mechanisms by which oncogenes deregulate DNA replication are not well understood. Using an assay to monitor nascent DNA synthesis in early S phase, Macheret and Halazonetis mapped replication initiation sites before and after induction of the oncogenes CCNE1 (which encodes cyclin E) and MYC to investigate the mechanisms underlying replication stress. Overexpressing CCNE1 or MYC shortened the G1 phase of the cell cycle and strongly induced a subset of DNA replication initiation sites, termed oncogene-induced (Oi) origins, that were not active in normal conditions. The Oi origins occurred predominantly in intragenic regions, compared with the constitutive origins, and there was an increase in Oi origin firing in the cells with the shortest G1 phases, indicative of premature entry into S phase. These findings suggest that oncogene induction induces firing of intragenic origins in regions normally devoid of replication initiation in cells exhibiting premature S phase entry. The Oi replication origins were enriched at highly transcribed genes; transcription was shown to inactivate intragenic origins before S phase entry, suggesting that early oncogene-induced entry into S phase may occur before transcription has completely suppressed Oi origins. Indeed, a high level of transcription at Oi origins was associated with replication fork collapse, likely caused by replication–transcription conflicts, that led to the formation of DNA double-strand breaks, providing a mechanism for the oncogene-mediated induction of replication stress. Taken together, these findings elucidate a mechanism by which oncogenes can induce replication stress in cancer; oncogene induction promotes premature entry into S phase and replication from intragenic origins, thereby increasing replication–transcription conflicts, promoting replication fork collapse, and inducing replication stress.
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