Bibliographic Details
| Title: |
A formamidopyrimidine derivative from the deoxyguanosine adduct produced by food contaminant acrylamide induces DNA replication block and mutagenesis. |
| Authors: |
Jun-ichi Akagi1 jun@nihs.go.jp, Masayuki Yokoi2, Yumi Miyake3, Tsuyoshi Shirai4, Tomohiro Baba5, Young-Man Cho1, Fumio Hanaoka2,6, Kaoru Sugasawa2, Shigenori Iwai5, Kumiko Ogawa1 |
| Source: |
Journal of Biological Chemistry. Aug2023, Vol. 299 Issue 8, p1-16. 16p. |
| Subject Terms: |
*DNA replication, *DEOXYGUANOSINE, *MUTAGENESIS, *DNA synthesis, *HUMAN DNA, *DNA polymerases, *ACRYLAMIDE, *DNA adducts |
| Abstract: |
Acrylamide, a common food contaminant, is metabolically activated to glycidamide, which reacts with DNA at the N7 position of dG, forming N7-(2-carbamoyl-2-hydroxyethyl)-dG (GA7dG). Owing to its chemical lability, the mutagenic potency of GA7dG has not yet been clarified. We found that GA7dG undergoes ring-opening hydrolysis to form N6-(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-[N-(2-carbamoyl-2-hydroxyethyl)formamido]pyrimidine (GA-FAPy-dG), even at neutral pH. Therefore, we aimed to examine the effects of GA-FAPy-dG on the efficiency and fidelity of DNA replication using an oligonucleotide carrying GA-FAPy–9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)guanine (dfG), a 2′-fluorine substituted analog of GA-FAPy-dG. GA-FAPy-dfG inhibited primer extension by both human replicative DNA polymerase ε and the translesion DNA synthesis polymerases (Polη, Polι, Polκ, and Polζ) and reduced the replication efficiency by less than half in human cells, with single base substitution at the site of GA-FAPy-dfG. Unlike other formamidopyrimidine derivatives, the most abundant mutation was G:C > A:T transition, which was decreased in Polκ- or REV1-KO cells. Molecular modeling suggested that a 2-carbamoyl-2-hydroxyethyl group at the N5 position of GA-FAPy-dfG can form an additional H-bond with thymidine, thereby contributing to the mutation. Collectively, our results provide further insight into the mechanisms underlying the mutagenic effects of acrylamide. [ABSTRACT FROM AUTHOR] |
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