High rate of starvation-associated mutagenesis in Ung− yeast caused by the overproduction of human activation-induced deaminase
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We examined the role of Saccharomyces cerevisiae uracil DNA glycosylase in the suppression of mutagenesis in non-dividing, adenine-starved cells expressing human activation-induced deaminase (AID) gene. Our aim was to further understand the mechanisms preventing starvation-associated mutagenesis in yeast and to explore the consequences of AID gene expression in non-proliferating eukaryotic cells. Genetic control of starvation-induced mutagenesis in many aspects is similar to the control of spontaneous logarithmic phase mutagenesis. Low DNA polymerase fidelity, defects of mismatch repair or post-replication repair lead to the elevation of mutagenesis. Less is known about the role of uracil in DNA. In yeast, the UNG1 gene codes for a uracil DNA glycosylase, which removes uracil from DNA, thus preventing an accumulation of mutations. The UNG1 gene is constitutively expressed at low levels throughout the cell cycle and peaks in late G1/early S phase. We have shown that the wild-type UNG1 allele protects from AID-induced mutations in starved cells to the same extent as it does in logarithmic growth phase cells. This finding implies that the first step in uracil removal by base excision repair (BER) is similar in these two conditions and provides the first data for understanding the role of BER in starvation-associated mutagenesis.
KeywordsStarvation-associated mutagenesis Cytosine deamination Activation-induced deaminase Uracil DNA glycosylase Saccharomyces cerevisiae
We are grateful to the University of Perugia (Italy), the University of Nebraska Medical Center (USA) and the University of Dubna (Russia) for the Cultural Agreement, which contributes to the exchange of researchers and, therefore, ideas between countries. We thank Ms. Kristi Berger (UNMC, Omaha, NE) for language editing.
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