Stimulation of sister chromatid exchanges and mutation by aflatoxin B 1-DNA adducts in sSaccharomyces cerevisiae requires MEC1 (ATR), RAD53, and DUN1

Michael Fasullo, Mingzeng Sun, Patricia Egner

Research output: Contribution to journalArticle

Abstract

The hepatocarcinogen aflatoxin B1 (AFB1) is a potent recombinagen but weak mutagen in the yeast Saccharomyces cerevisiae. AFB 1 exposure induces DNA damage-inducible genes, such as RAD51 and those encoding ribonucleotide reductase (RNR), through a MEC1 (ATR homolog)-dependent pathway. Previous studies have indicated that MEC1 is required for both AFB1-associated recombination and mutation, and suggested that AFB1-DNA adduces are common substrates for recombination and mutagenesis. However, little is known about the downstream effectors of MEC1 required for genotoxic events associated with AFB1 exposure. Here we show that AFB1 exposure increases frequencies of RAD51-dependent unequal sister chromatid exchange (SCE) and activates Rad53 (CHK2). We found that MEC1, RAD53, and DUN1 are required for both AFB 1-associated mutation and SCE. Deletion of SML1, which encodes an inhibitor of RNR, did not suppress the DUN1-dependent requirement for AFB 1-associated genetic events, indicating that higher dNTP levels could not suppress the dun1 phenotype. We identified AFB1-DNA adducts and show that approximately the same number of adducts are obtained in both wild type and rad53 mutants. Since DUN1 is not required for UV-associated mutation and recombination, these studies define a distinct role for DUN1 in AFB 1-associated mutagenesis and recombination. We speculate that AFB1-associated DNA adducts stall DNA replication, a consequence of which can either be mutation or recombination.

Original languageEnglish (US)
Pages (from-to)608-615
Number of pages8
JournalMolecular Carcinogenesis
Volume47
Issue number8
DOIs
StatePublished - Aug 1 2008

Keywords

  • Aflatoxin B
  • Cell-cycle checkpoint
  • DNA adducts
  • Mutation recombination
  • Saccharomyces cerevisiae

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Stimulation of sister chromatid exchanges and mutation by aflatoxin B <sub>1</sub>-DNA adducts in sSaccharomyces cerevisiae requires MEC1 (ATR), RAD53, and DUN1'. Together they form a unique fingerprint.

  • Cite this