NCOA4 Transcriptional Coactivator Inhibits Activation of DNA Replication Origins

被引：67

作者：

Bellelli, Roberto ^{[1
]}

Castellone, Maria Domenica ^{[1
]}

Guida, Teresa ^{[1
]}

Limongello, Roberto ^{[1
]}

Dathan, Nina Alayne ^{[2
]}

Merolla, Francesco ^{[1
]}

Cirafici, Anna Maria ^{[1
]}

Affuso, Andrea ^{[3
]}

Masai, Hisao ^{[4
]}

Costanzo, Vincenzo ^{[5
]}

Grieco, Domenico ^{[1
]}

Fusco, Alfredo ^{[1
]}

Santoro, Massimo ^{[1
]}

Carlomagno, Francesca ^{[1
]}

机构：

[1] Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, CNR, Ist Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy

[2] CNR, Ist Biostrutture & Bioimmagini, I-80134 Naples, Italy

[3] Biogem Scarl, Anim Model Facil, I-83031 Avellino, Italy

[4] Tokyo Metropolitan Inst Med Sci, Tokyo 1568506, Japan

[5] London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England

来源：

MOLECULAR CELL | 2014年 / 55卷 / 01期

关键词：

ANDROGEN RECEPTOR; DAMAGE RESPONSE; QUANTITATIVE PROTEOMICS; GENOME STABILITY; PROSTATE-CANCER; HUMAN-CELLS; HELICASE; INITIATION; CDC45; XENOPUS;

D O I：

10.1016/j.molcel.2014.04.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：123 / 137

页数：15

共 52 条

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