Publication Date:
2015-06-24
Description:
Etheno DNA adducts are a prevalent type of DNA damage caused by vinyl chloride (VC) exposure and oxidative stress. Etheno adducts are mutagenic and may contribute to the initiation of several pathologies; thus, elucidating the pathways by which they induce cellular transformation is critical. Although N 2 ,3-ethenoguanine ( N 2 ,3-G) is the most abundant etheno adduct, its biological consequences have not been well characterized in cells due to its labile glycosidic bond. Here, a stabilized 2'-fluoro-2'-deoxyribose analog of N 2 ,3-G was used to quantify directly its genotoxicity and mutagenicity. A multiplex method involving next-generation sequencing enabled a large-scale in vivo analysis, in which both N 2 ,3-G and its isomer 1, N 2 -ethenoguanine (1, N 2 -G) were evaluated in various repair and replication backgrounds. We found that N 2 ,3-G potently induces G to A transitions, the same mutation previously observed in VC-associated tumors. By contrast, 1, N 2 -G induces various substitutions and frameshifts. We also found that N 2 ,3-G is the only etheno lesion that cannot be repaired by AlkB, which partially explains its persistence. Both G lesions are strong replication blocks and DinB, a translesion polymerase, facilitates the mutagenic bypass of both lesions. Collectively, our results indicate that N 2 ,3-G is a biologically important lesion and may have a functional role in VC-induced or inflammation-driven carcinogenesis.
Keywords:
Mutagenesis
Print ISSN:
0305-1048
Electronic ISSN:
1362-4962
Topics:
Biology
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