HAM1, the gene controlling 6-N-hydroxylaminopurine sensitivity and mutagenesis in the yeast Saccharomyces cerevisiae

Genome-wide screening for genes whose deletions confer sensitivity to mutagenic purine base analogs in yeast

“…Previously we observed that the inactivation of the APT1 gene, encoding adenine phosphoribosyl transferase, led to a severe decrease of the mutagenic effect of HAP [16], suggesting that this enzyme plays a key role in the biosynthesis of HAP-riboside-5'-monophosphate (HAPMP). HAPMP then may be converted to the corresponding nucleoside triphosphate, which could be ambiguously incorporated into DNA by DNA polymerases and provoke replication errors in the subsequent replication cycles [13]. …”

“…It was proposed that purine salvage enzymes convert base analogs to the corresponding deoxyribonucleoside triphosphates, which are misincorporated or misreplicated during DNA synthesis, resulting in induction of mutations [12,13]. HAP-induced mutagenesis in yeast is elevated in strains with defects in proofreading activity of replicative DNA polymerases [14,15] and does not depend on excision, mutagenic recombination, and mismatch repair systems [14-16].…”

“…We initially described the elevated sensitivity to HAP in yeast due to mutations in the HAM1 gene [18]. When we cloned and sequenced the HAM1 gene, we found that it has homologs in many organisms, from bacteria to humans [13], and proposed that the gene might code for new triphosphatase [16]. Then, the crystal structure of the Ham1p homologue from a thermostable bacterium (protein Mj0226) was determined [19].…”

Molecular Basis of the Antimutagenic Activity of the House-Cleaning Inosine Triphosphate Pyrophosphatase RdgB from Escherichia coli

“…Most ITPases belong to the HAM1 family (IPR002637; 682 sequences in databases) named after the hydroxylaminopurine sensitivity protein-1 from yeasts. 6 In Saccharomyces cerevisiae, the HAM1 protein protects against the mutagenic effects of the base analog hydroxylaminopurine, which is a natural product of monoxygenase activity on adenine. 6 Only three HAM1 proteins-ITPA from humans, MJ0226 from Methanococcus jannaschii, and RdgB from Escherichia coli-have been biochemically characterized.…”

“…6 In Saccharomyces cerevisiae, the HAM1 protein protects against the mutagenic effects of the base analog hydroxylaminopurine, which is a natural product of monoxygenase activity on adenine. 6 Only three HAM1 proteins-ITPA from humans, MJ0226 from Methanococcus jannaschii, and RdgB from Escherichia coli-have been biochemically characterized. [7][8][9][10] These proteins showed activity against both canonical and noncanonical nucleotides, but the latter was hydrolyzed 10-100 times more efficiently.…”