The aflatoxin B1-induced imidazole ring-opened guanine adduct: High mutagenic potential that is minimally affected by sequence context

Irina G. Minko, Andrew H. Kellum, Michael P. Stone, R. Stephen Lloyd

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Dietary exposure to aflatoxin B1 (AFB1) is a recognized risk factor for developing hepatocellular carcinoma. The mutational signature of AFB1 is characterized by high-frequency base substitutions, predominantly G>T transversions, in a limited subset of trinucleotide sequences. The 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B1 (AFB1-FapyGua) has been implicated as the primary DNA lesion responsible for AFB1-induced mutations. This study evaluated the mutagenic potential of AFB1-FapyGua in four sequence contexts, including hot- and cold-spot sequences as apparent in the mutational signature. Vectors containing site-specific AFB1-FapyGua lesions were replicated in primate cells and the products of replication were isolated and sequenced. Consistent with the role of AFB1-FapyGua in AFB1-induced mutagenesis, AFB1-FapyGua was highly mutagenic in all four sequence contexts, causing G>T transversions and other base substitutions at frequencies of ~80%–90%. These data suggest that the unique mutational signature of AFB1 is not explained by sequence-dependent fidelity of replication past AFB1-FapyGua lesions.

Original languageEnglish (US)
Pages (from-to)9-13
Number of pages5
JournalEnvironmental and Molecular Mutagenesis
Volume65
Issue numberS1
DOIs
StatePublished - Apr 2024

Keywords

  • COSMIC signature SBS24
  • base substitution
  • hepatocellular carcinoma
  • replication bypass

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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