Lethal accumulation of guanylic nucleotides in Saccharomyces cerevisiae HPT1-deregulated mutants

Genetics. 2008 Feb;178(2):815-24. doi: 10.1534/genetics.107.083295. Epub 2008 Feb 3.


Guanylic nucleotide biosynthesis is a conserved and highly regulated process. Drugs reducing GMP synthesis affect the immunological response and mutations enabling guanylic-derivative recycling lead to severe mental retardation. While the effects of decreased GMP synthesis have been well documented, the consequences of GMP overproduction in eukaryotes are poorly understood. In this work, we selected and characterized several mutations making yeast hypoxanthine-guanine phosphoribosyltransferase insensitive to feedback inhibition by GMP. In these mutants, accumulation of guanylic nucleotides can be triggered by addition of extracellular guanine. We show that such an accumulation is highly toxic for yeast cells and results in arrest of proliferation and massive cell death. This growth defect could be partially suppressed by overexpression of Rfx1p, a transcriptional repressor of the DNA damage response pathway. Importantly, neither guanylic nucleotide toxicity nor its suppression by Rfx1p was associated with an alteration of forward mutation frequency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Primers
  • Escherichia coli / genetics
  • Gene Expression Regulation, Fungal*
  • Genes, Lethal*
  • Guanine Nucleotides / biosynthesis
  • Guanine Nucleotides / metabolism*
  • Guanosine Monophosphate / metabolism
  • Guanosine Monophosphate / pharmacology
  • Hypoxanthine Phosphoribosyltransferase / genetics*
  • Hypoxanthine Phosphoribosyltransferase / metabolism
  • Mutagenesis
  • Mutation*
  • Plasmids
  • Polymerase Chain Reaction
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics*


  • DNA Primers
  • Guanine Nucleotides
  • Saccharomyces cerevisiae Proteins
  • Guanosine Monophosphate
  • Hypoxanthine Phosphoribosyltransferase