title: NCOA4 transcriptional coactivator inhibits activation of DNA replication origins.
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.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bellelli
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Castellone
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Guida
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Limongello
authors.affiliation: Istituto di Biostrutture e Bioimmagini del CNR, 80134 Naples, Italy.
authors.forename: Nina Alayne
authors.initials: NA
authors.lastname: Dathan
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merolla
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cirafici
authors.affiliation: Animal Model Facility, Biogem s.c.a.r.l., 83031 Ariano Irpino, Avellino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Affuso
authors.affiliation: Tokyo Metropolitan Institute of Medical Sciences, 156-8506 Tokyo, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Masai
authors.affiliation: London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Grieco
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D004261:DNA Replication; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D064168:Minichromosome Maintenance Complex Component 7 / Q000378:metabolism; D056918:Nuclear Receptor Coactivators / Q000378:metabolism / Q000502:physiology*; D018741:Replication Origin; D020798:Two-Hybrid System Techniques; D014982:Xenopus laevis
chemical_list: C111382:NCOA4 protein, human; C508724:NcoA4 protein, mouse; D056918:Nuclear Receptor Coactivators; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7