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

Abstract

Consumption of foods contaminated with aflatoxin B (AFB) is a recognized risk factor for developing hepatocellular carcinomas (HCCs). The mutational signature of AFB is characterized by high frequency 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 B (AFB-FapyGua) has been implicated as the primary DNA lesion responsible for AFB-induced mutations. This study evaluated the mutagenic potential of AFB-FapyGua in four contexts, including hot- and cold-spot sequences as apparent in the mutational signature. Vectors containing AFB-FapyGua were replicated in primate cells and the products of replication were isolated and sequenced. Regardless of the sequence context, AFB-FapyGua caused base substitutions at frequencies of ~ 80-90%, with G > T transversions being most common. Spectra of mutations were only slightly modulated by the sequence context. These data suggest that mechanism(s) defining sequence context-dependent distribution of AFB-induced mutations likely operates prior to replication.

Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing

“…In addition, pol η and pol κ have the potential to contribute to mutagenic bypass of both the initial N7-dG and Fapy lesions ( 33 , 64 ). Consistent with an extremely error-prone bypass of AFB 1 -induced adducts observed in vitro , the biological consequences of blocked replication and subsequent translesion synthesis past these lesions are high frequency SBS, predominantly G > T transversions ( 33 , 34 , 64 ). Although these spectra strongly correlate with the mutagenic outcome of AFB 1 exposure ( 12 , 14–17 , 30 , 62 ), they have been shown to be only minimally modulated by sequence context.…”

“…The AFB 1 -Fapy-dG lesion is persistent in vivo ( 25 , 28–32 ). The persistence, along with the known potential to cause high frequency base substitutions (80–90%), predominated by G > T transversions ( 33 , 34 ) implicate AFB 1 -Fapy-dG as a major contributor to AFB 1 -induced mutagenesis.…”

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

“…This SI is to promote recent findings and advances on genome integrity mechanisms 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.…”

“…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).…”

“…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).…”