Multiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts

Nat Commun. 2018 Jan 25;9(1):379. doi: 10.1038/s41467-017-02756-x.

Abstract

Conflicts between replication and transcription machineries represent a major source of genomic instability and cells have evolved strategies to prevent such conflicts. However, little is known regarding how cells cope with sudden increases of transcription while replicating. Here, we report the existence of a general mechanism for the protection of genomic integrity upon transcriptional outbursts in S phase that is mediated by Mrc1. The N-terminal phosphorylation of Mrc1 blocked replication and prevented transcription-associated recombination (TAR) and genomic instability during stress-induced gene expression in S phase. An unbiased kinome screening identified several kinases that phosphorylate Mrc1 at the N terminus upon different environmental stresses. Mrc1 function was not restricted to environmental cues but was also required when unscheduled transcription was triggered by low fitness states such as genomic instability or slow growth. Our data indicate that Mrc1 integrates multiple signals, thereby defining a general safeguard mechanism to protect genomic integrity upon transcriptional outbursts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • DNA Replication*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Regulation, Fungal*
  • Genomic Instability*
  • Glucose / deficiency
  • Hot Temperature
  • Hydrogen Peroxide / pharmacology
  • Osmotic Pressure
  • Oxidative Stress / genetics
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • S Phase
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction
  • Sodium Chloride / pharmacology
  • Transcription, Genetic*

Substances

  • Cell Cycle Proteins
  • MRC1 protein, S cerevisiae
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • Sodium Chloride
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • Glucose