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, consequences of GMP overproduction in eucaryotes 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 over expression of Rfx1p, a transcriptional repressor of the DNA damage response pathway. Importantly, neither guanylic nucleotide toxicity nor its suppression by Rfx1p were associated with an alteration of forward mutation frequency.

Key Words: Guanylic nucleotides, HGPRT, deregulated mutants, feedback control

Online ISS 1091-6490
Copyright 2008 by the Genetics Society of America
phone: 412-268-1812   fax: 412-268-1813   email: genetics-gsa{at}andrew.cmu.edu