Vulnerable Nucleotide Pools and Genomic Instability in Yeast Strains with Deletion of the ADE12 Gene Encoding for Adenylosuccinate Synthetase

Adenylosuccinate synthetase (AdSS), encoded by the <i>ADE12</i> gene in yeast <i>Saccharomyces cerevisiae,</i> plays a critical role in purine biosynthesis, catalyzing the conversion of inosine 5'-monophosphate (IMP) and aspartic acid to adenylosuccinate, a substrate for the following adenosine 5'-monophosphate (AMP) synthesis step. Mutants lacking AdSS activity exhibit a range of pleiotropic phenotypes: slow growth, poor spore germination, accumulation, and secretion of inosine and hypoxanthine. We report new phenotypes of <i>ade12</i> mutants and explain their molecular mechanisms. A GC-MS analysis showed that <i>ade12</i> mutants have highly altered metabolite profiles: the accumulation of IMP leads to an impaired cellular energy metabolism, resulting in a dysregulation of key processes-the metabolism of nucleotides, carbohydrates, and amino acids. These metabolic perturbations explain the cell division arrest observed in <i>ade12</i> yeast strains. A slowed replication in <i>ade12</i> mutants, because of the insufficient availability of energy, nucleotides, and proteins, leads to the error-prone DNA polymerase ζ-dependent elevation of spontaneous mutagenesis, connecting multiple roles of AdSS in metabolism with genome stability control.