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Rev1 and Polzeta influence toxicity and mutagenicity of Me-lex, a sequence selective N3-adenine methylating agent.

Abstract
The relative toxicity and mutagenicity of Me-lex, which selectively generates 3-methyladenine (3-MeA), is dependent on the nature of the DNA repair background. Base excision repair (BER)-defective S. cerevisiae strains mag1 and apn1apn2 were both significantly more sensitive to Me-lex toxicity, but only the latter is significantly more prone to Me-lex-induced mutagenesis. To examine the contribution of translesion synthesis (TLS) DNA polymerases in the bypass of Me-lex-induced lesions, the REV3 and REV1 genes were independently deleted in the parental yeast strain and in different DNA repair-deficient derivatives: the nucleotide excision repair (NER)-deficient rad14, and the BER-deficient mag1 or apn1apn2 strains. The strains contained an integrated ADE2 reporter gene under control of the transcription factor p53. A centromeric yeast expression vector containing the wild-type p53 cDNA was treated in vitro with increasing concentrations of Me-lex and transformed into the different yeast strains. The toxicity of Me-lex-induced lesions was evaluated based on the plasmid transformation efficiency compared to the untreated vector, while Me-lex mutagenicity was assessed using the p53 reporter assay. In the present study, we demonstrate that disruption of Polzeta (through deletion of its catalytic subunit coded by REV3) or Rev1 (by REV1 deletion) increased Me-lex lethality and decreased Me-lex mutagenicity in both the NER-defective (rad14) and BER-defective (mag1; apn1apn2) strains. Therefore, Polzeta and Rev1 contribute to resistance of the lethal effects of Me-lex-induced lesions (3-MeA and derived AP sites) by bypassing lesions and fixing some mutations.
AuthorsPaola Monti, Yari Ciribilli, Debora Russo, Alessandra Bisio, Chiara Perfumo, Virginia Andreotti, Paola Menichini, Alberto Inga, Xiaofen Huang, Barry Gold, Gilberto Fronza
JournalDNA repair (DNA Repair (Amst)) Vol. 7 Issue 3 Pg. 431-8 (Mar 1 2008) ISSN: 1568-7864 [Print] Netherlands
PMID18182332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimutagenic Agents
  • Mutagens
  • RAD14 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Tumor Suppressor Protein p53
  • methyl lexitropsin
  • 3-methyladenine
  • Netropsin
  • DNA polymerase zeta
  • Nucleotidyltransferases
  • REV1 protein, S cerevisiae
  • DNA-Directed DNA Polymerase
  • REV3 protein, S cerevisiae
  • Endodeoxyribonucleases
  • Apn1 protein, S cerevisiae
  • DNA Glycosylases
  • MAG1 protein, S cerevisiae
  • APN2 protein, S cerevisiae
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • DNA Repair Enzymes
  • Adenine
Topics
  • Adenine (analogs & derivatives, chemistry)
  • Antimutagenic Agents (pharmacology)
  • Cell Survival (drug effects, physiology)
  • DNA Glycosylases (genetics, metabolism)
  • DNA Methylation (drug effects)
  • DNA Repair (physiology)
  • DNA Repair Enzymes
  • DNA-(Apurinic or Apyrimidinic Site) Lyase (genetics, metabolism)
  • DNA-Directed DNA Polymerase (genetics, metabolism)
  • Endodeoxyribonucleases (genetics, metabolism)
  • Mutagens (toxicity)
  • Netropsin (analogs & derivatives, toxicity)
  • Nucleotidyltransferases (genetics, metabolism)
  • Saccharomyces cerevisiae (genetics, growth & development, metabolism)
  • Saccharomyces cerevisiae Proteins (genetics, metabolism)
  • Tumor Suppressor Protein p53

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