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NCOA4 transcriptional coactivator inhibits activation of DNA replication origins

Roberto Bellelli1, Maria Domenica Castellone1, Teresa Guida1

  • 1Istituto di Endocrinologia ed Oncologia Sperimentale del CNR/Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Naples, Italy.

Molecular Cell
|June 10, 2014
PubMed

Insights

Nuclear receptor coactivator NCOA4 regulates DNA replication origins, preventing replication stress. Its absence causes unscheduled origin activation and fork stalling, leading to premature senescence.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Nuclear receptor coactivator 4 (NCOA4) is involved in nuclear hormone receptor activity and gene rearrangement in cancer.
  • DNA replication is a fundamental process tightly regulated to ensure genomic stability.

Purpose of the Study:

  • To investigate the role of NCOA4 in DNA replication control.
  • To elucidate the mechanism by which NCOA4 influences DNA replication origin activation and prevents replication stress.

Main Methods:

  • Studies were conducted using Xenopus laevis egg extracts and mouse embryonic fibroblasts (MEFs).
  • Depletion-reconstitution experiments were performed in Xenopus laevis egg extracts.
  • NCOA4 knockout (NCOA4(-/-)) MEFs were analyzed for DNA replication phenotypes.

Main Results:

  • NCOA4 interacts with minichromosome maintenance 7 (MCM7) and controls DNA replication.
  • NCOA4 inhibits DNA replication origin activation by regulating the CMG (CDC45/MCM2-7/GINS) helicase.
  • NCOA4(-/-) MEFs exhibit unscheduled origin activation, reduced interorigin distance, fork stalling, decreased fork speed, and premature senescence.

Conclusions:

  • NCOA4 functions as a crucial regulator of DNA replication origins.
  • NCOA4 plays a vital role in preventing inappropriate DNA synthesis and replication stress, thereby maintaining genomic integrity.

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