University of North Carolina at Pembroke

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Nucleotide Excision Repair Defect Influences Lethality and Mutagenicity Induced by Me-lex, a Sequence-Selective N3-Adenine Methylating Agent in the Absence of Base Excision Repair

Paola Monti; Raffaella Iannone; Paola Campomenosi; Yari Ciribilli; Sridhar Varadarajan; Dharini Shah; Paola Menichini; Barry Gold; Gilberto Fronza (Profiled Author: Sridhar Varadarajan)

Biochemistry. 2004;43(19):5592-5599.

Using a yeast shuttle vector system, we have previously reported on the toxicity and mutagenicity of Me-lex, {1-methyl-4-[1-methyl-4-[3-(methoxysulfonyl)propanamido]pyrrole-2-carboxamido] pyrrole-2-carboxamido}propane, a compound that selectively generates 3-methyladenine (3-MeA). We observed that a mutant strain defective in Mag1, the glycosylase that excises 3-MeA in the initial step of base excision repair (BER) to generate an abasic site, is significantly more sensitive to the toxicity of Me-lex with respect to wild type but shows only a marginal increase in mutagenicity. A strain defective in AP endonuclease activity (Δapn1apn2), also required for functional BER, is equally sensitive to the toxicity as the Δmag1 mutant but showed a significantly higher mutation frequency. In the present work, we have explored the role of nucleotide excision repair (NER) in Me-lex-induced toxicity and mutagenicity since it is known that NER acts on abasic sites in vivo in yeast and in vitro assays. To accomplish this, we have deleted one of the genes essential for NER in yeast, namely, RAD14, both in the context of an otherwise DNA repair-proficient strain (Δrad14) and in a BER-defective isogenic derivative lacking the MAG1 gene (Δmag1rad14). Interestingly, no sensitivity to the treatment with Me-lex was conferred by the simple deletion of RAD14. However, a significant enhancement in toxicity and mutagenicity was observed when cells lacked both Rad14 and Mag1. The mutation spectrum induced by Me-lex in the Δmag1rad14 strain is indistinguishable from that observed in the Δapn1/Δpn2 or in the Δmag1 strains. The results indicate that in yeast NER can play a protective role against 3-MeA-mediated toxicity and mutagenicity; however, the role of NER is appreciable only in a BER-defective background.

PMID: 15134433    

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