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Mol Cell. 2014 Jul 3;55(1):123-37. doi: 10.1016/j.molcel.2014.04.031. Epub 2014 Jun 5.

NCOA4 transcriptional coactivator inhibits activation of DNA replication origins.

Author information

1
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
2
Istituto di Biostrutture e Bioimmagini del CNR, 80134 Naples, Italy.
3
Animal Model Facility, Biogem s.c.a.r.l., 83031 Ariano Irpino, Avellino, Italy.
4
Tokyo Metropolitan Institute of Medical Sciences, 156-8506 Tokyo, Japan.
5
London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, UK.
6
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy. Electronic address: masantor@unina.it.
7
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy. Electronic address: persfra@tin.it.

Abstract

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.

PMID:
24910095
DOI:
10.1016/j.molcel.2014.04.031
[Indexed for MEDLINE]
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