Lethal accumulation of guanylic nucleotides in Saccharomyces cerevisiae HPT1-deregulated mutants.
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.
Breton
Annick
A
Université Victor Segalen/Bordeaux, 33077 Bordeaux, France.
Pinson
Benoît
B
Coulpier
Fanny
F
Giraud
Marie-France
MF
Dautant
Alain
A
Daignan-Fornier
Bertrand
B
D017931:DNA Primers; D004926:Escherichia coli / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D005804:Genes, Lethal; D006150:Guanine Nucleotides / Q000096:biosynthesis / Q000378:metabolism*; D006157:Guanosine Monophosphate / Q000378:metabolism / Q000494:pharmacology; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
D017931:DNA Primers; D006150:Guanine Nucleotides; D029701:Saccharomyces cerevisiae Proteins; D006157:Guanosine Monophosphate; D007041:Hypoxanthine Phosphoribosyltransferase