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 language | English (US) |
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Pages (from-to) | 9-13 |
Number of pages | 5 |
Journal | Environmental and Molecular Mutagenesis |
Volume | 65 |
Issue number | S1 |
DOIs | |
State | Published - Apr 2024 |
Keywords
- COSMIC signature SBS24
- base substitution
- hepatocellular carcinoma
- replication bypass
ASJC Scopus subject areas
- Epidemiology
- Genetics(clinical)
- Health, Toxicology and Mutagenesis