NCOA4 transcriptional coactivator inhibits activation of DNA replication origins

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Senescence
  • DNA Replication*
  • HeLa Cells
  • Humans
  • Mice
  • Minichromosome Maintenance Complex Component 7 / metabolism
  • Nuclear Receptor Coactivators / metabolism
  • Nuclear Receptor Coactivators / physiology*
  • Replication Origin*
  • Two-Hybrid System Techniques
  • Xenopus laevis

Substances

  • NCOA4 protein, human
  • NcoA4 protein, mouse
  • Nuclear Receptor Coactivators
  • MCM7 protein, human
  • Minichromosome Maintenance Complex Component 7