Abstract
Carcinogens often generate mutable DNA lesions that contribute to cancer and aging. However, the chemical structure of tumorigenic DNA lesions formed by acetaldehyde remains unknown, although it has long been considered an environmental mutagen in alcohol, tobacco, and food. Here, we identify an aldehyde-induced DNA lesion, forming an intrastrand crosslink between adjacent guanine bases, but not in single guanine bases or in other combinations of nucleotides. The GG intrastrand crosslink exists in equilibrium in the presence of aldehyde, and therefore it has not been detected or analyzed in the previous investigations. The newly identified GG intrastrand crosslinks might explain the toxicity and mutagenicity of acetaldehyde in DNA metabolism.
Highlights
Acetaldehyde is a small, highly reactive compound that occurs naturally in various plants, ripe fruits, and vegetables, and is a key raw material in a wide range of chemical products
We found that acetaldehyde reacts with single-stranded or double-stranded oligonucleotides containing GG, but not TT, GT, GA, AG, GC, or CG
Mass analysis revealed that acetaldehyde forms GG intrastrand crosslinks, a new type of DNA lesion that is uniquely reversible
Summary
Acetaldehyde is a small, highly reactive compound that occurs naturally in various plants, ripe fruits, and vegetables, and is a key raw material in a wide range of chemical products. Acetaldehyde reacts with deoxyguanosine to form N2-ethylidenedeoxyguanosine, a type of Schiff base adduct[8,9]. One hint for the identity of mutagenic lesions caused by acetaldehyde comes from a test of mutagenicity, in which a plasmid containing a selectable drug resistance gene is incubated with acetaldehyde in vitro and transfected into human cells. This revealed an increase of GG to TT mutations in NER-deficient human XP cells[12]. Detailed analysis revealed that acetaldehyde forms reversible intrastrand crosslinks in GG These lesions are unstable, and have not been previously observed, but are likely to be toxic and mutagenic. We propose that these GG lesions may account for the apparent carcinogenicity of acetaldehyde in humans, and our understanding of these lesions may help develop new strategies to prevent alcohol-related cancer
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