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

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.

Inspiring basic and applied research in genome integrity mechanisms: Dedication to Samuel H. Wilson

“…with emphasis on their importance for basic and environmental health sciences. This SI includes two research articles, one brief communication, and four reviews (Hoag et al, 2024;Hua & Sweasy, 2024;Hussen et al, 2024;Minko et al, 2024;Sobol, 2024;Stroik et al, 2024;Wilson & Wyrick, 2024). The findings and perspectives from this SI may help to better understand how DNA damage and DNA repair mechanisms can provide novel insights into environmentally-induced human disease such as cancer.…”

“…Taking advantage of site-specifically modified vectors containing AFB1-FapyGua in four different local sequences (i.e., AXC, CXC, TXC, and CXA. X represents AFB1-FapyGua), Minko et al found that AFB1-FapyGua led to a high frequency of mutagenesis (80%-90%) in all four sequence contexts with G > T transversions as the major type of mutation (Minko et al, 2024). The authors also discussed the potential roles of the DNA replication machinery, translesion DNA synthesis polymerases, and DNA repair mechanisms in AFB1-FapyGua-induced mutagenesis (Minko et al, 2024).…”

“…In a brief communication, the Lloyd and Stone laboratories reported that guanine adducts from dietary exposure to aflatoxin B1 (AFB1) can lead to high mutagenic G > T transversions and other base substitutions in a trinucleotide-sequence-independent manner (Minko et al, 2024). AFB1 can cause the single base substitution mutation signature SBS 24, and represents a significant risk factor for cancer development (Alexandrov et al, 2020;McCullough & Lloyd, 2019).…”