NCOA4 Transcriptional Coactivator Inhibits Activation of DNA Replication Origins

• NCOA4 protein interacts with the CMG (CDC45/MCM2–7/GINS) helicase via MCM7
• NCOA4 binds to canonical DNA replication origins in mammalian cells
• NCOA4 hinders CMG helicase and blocks DNA replication origin activation
• NCOA4 depletion in primary mammalian cells leads to replication stress

SummaryNCOA4 is a transcriptional coactivator of nuclear hormone receptors that undergoes gene rearrangement in human cancer. By combining studies in Xenopus laevis egg extracts and mouse embryonic fibroblasts (MEFs), we show here that NCOA4 is a minichromosome maintenance 7 (MCM7)-interacting protein that is able to control DNA replication. Depletion-reconstitution experiments in Xenopus laevis egg extracts indicate that NCOA4 acts as an inhibitor of DNA replication origin activation by regulating CMG (CDC45/MCM2–7/GINS) helicase. NCOA4−/− MEFs display unscheduled origin activation and reduced interorigin distance; this results in replication stress, as shown by the presence of fork stalling, reduction of fork speed, and premature senescence. Together, our findings indicate that NCOA4 acts as a regulator of DNA replication origins that helps prevent inappropriate DNA synthesis and replication stress.

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