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Originally published as Genetics Published Articles Ahead of Print on February 3, 2008.

Genetics, Vol. 178, 815-824, February 2008, Copyright © 2008
doi:10.1534/genetics.107.083295

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Lethal Accumulation of Guanylic Nucleotides in Saccharomyces cerevisiae HPT1-Deregulated Mutants

Annick Breton*,{dagger}, Benoît Pinson*,{dagger}, Fanny Coulpier{ddagger}, Marie-France Giraud*,{dagger}, Alain Dautant*,{dagger} and Bertrand Daignan-Fornier*,{dagger},1

* Université Victor Segalen/Bordeaux 2, Institut de Biochimie et Génétique Cellulaires, 33077 Bordeaux, France, {dagger} CNRS, UMR 5095, 33077 Bordeaux, France and {ddagger} IFR36, Plate-forme Transcriptome, École Normale Supérieure, 75230 Paris, France

1 Corresponding author: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095 1, rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France.
E-mail: b.daignan-fornier{at}ibgc.u-bordeaux2.fr

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.


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