期刊
MOLECULAR CELL
卷 55, 期 1, 页码 123-137出版社
CELL PRESS
DOI: 10.1016/j.molcel.2014.04.031
关键词
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资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- European Community
- Regione Campania (project CREME)
- Italian Ministero per l'Istruzione, Universita e Ricerca Scientifica (MIUR)
- Grants-in-Aid for Scientific Research [23657081] Funding Source: KAKEN
NCOA4 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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