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DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1

Anna Travesa1, Dwight Kuo, Robertus A M de Bruin

  • 1Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.

The EMBO Journal
|February 16, 2012
PubMed

Insights

Genotoxic stress during S phase activates MBF-regulated genes by preventing Nrm1 binding. This checkpoint activation enhances DNA replication and repair, promoting genome stability.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • MBF and SBF transcription factors control G1/S genes essential for DNA replication and repair.
  • SBF is inactivated by Clb/CDK upon S-phase entry, while MBF targets are repressed by Nrm1.

Purpose of the Study:

  • To investigate how genotoxic stress during S phase affects MBF and SBF-regulated genes.
  • To elucidate the mechanism by which the S-phase checkpoint regulates MBF targets.

Main Methods:

  • Genome-wide expression analysis.
  • Treatment of cells with genotoxic agents: methyl methane sulfonate (MMS), hydroxyurea (HU), and camptothecin (CPT).

Main Results:

  • Genotoxic stress specifically induces MBF-regulated genes during S phase.
  • Rad53, an effector checkpoint kinase, phosphorylates Nrm1, preventing its promoter binding.
  • This mechanism distinguishes MBF-regulated genes by their sensitivity to S-phase checkpoint activation.

Conclusions:

  • MBF-regulated genes are activated by the S-phase checkpoint under genotoxic stress.
  • This activation enhances DNA replication and repair processes.
  • The findings provide a mechanism for promoting genome stability during S phase.

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