Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase

Cell. 2003 Feb 7;112(3):391-401. doi: 10.1016/s0092-8674(03)00075-8.

Abstract

In eukaryotes, DNA damage elicits a multifaceted response that includes cell cycle arrest, transcriptional activation of DNA repair genes, and, in multicellular organisms, apoptosis. We demonstrate that in Saccharomyces cerevisiae, DNA damage leads to a 6- to 8-fold increase in dNTP levels. This increase is conferred by an unusual, relaxed dATP feedback inhibition of ribonucleotide reductase (RNR). Complete elimination of dATP feedback inhibition by mutation of the allosteric activity site in RNR results in 1.6-2 times higher dNTP pools under normal growth conditions, and the pools increase an additional 11- to 17-fold during DNA damage. The increase in dNTP pools dramatically improves survival following DNA damage, but at the same time leads to higher mutation rates. We propose that increased survival and mutation rates result from more efficient translesion DNA synthesis at elevated dNTP concentrations.

Publication types

  • Comment

MeSH terms

  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism
  • Binding Sites / genetics
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / genetics*
  • Cell Survival / radiation effects
  • DNA / biosynthesis
  • DNA / genetics
  • DNA Damage / drug effects
  • DNA Damage / genetics*
  • DNA Damage / radiation effects
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • DNA Repair / radiation effects
  • Deoxyribonucleosides / genetics
  • Deoxyribonucleosides / metabolism*
  • Eukaryotic Cells / enzymology*
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / genetics
  • Feedback, Physiological / radiation effects
  • Gene Expression Regulation, Fungal / drug effects
  • Gene Expression Regulation, Fungal / genetics
  • Gene Expression Regulation, Fungal / radiation effects
  • Mutagens / pharmacology
  • Mutation / drug effects
  • Mutation / genetics
  • Mutation / radiation effects
  • Ribonucleotide Reductases / genetics
  • Ribonucleotide Reductases / metabolism*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Deoxyribonucleosides
  • Mutagens
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphate
  • DNA
  • Ribonucleotide Reductases