Conformation-Dependent Lesion Bypass and Mutagenicity of Bulky 2-Acetylaminofluorene-Guanine DNA Adduct in Epigenetically Relevant Sequence Contexts.

Abstract

DNA base cytosine can be modified epigenetically by adding a methyl group to form 5-methylcytosine (5mC). 5mC in DNA CpG islands plays a crucial role in mammalian cell development and epigenetic regulation. While 5mC does not block DNA replication and is not mutagenic, the biological consequences of 5mC affecting the flanking guanine with a bulky modification during DNA replication are not well understood. This paper examined the lesion bypass and mutagenicity of the 2-acetylaminofluorene-modified guanine DNA adduct (dG-AAF) in epigenetically relevant sequence contexts in Escherichia coli. The C/5mC context exhibited significantly different bypass and mutagenicity profiles for dG-AAF. The biological outcomes also varied depending on the nature of the 3' flanking base and the lesion bulkiness. In addition, we extensively observed a unique type of -1 G deletion when the lesion was flanked by 3' purines, possibly due to the formation of a stacked slipped mutagenic intermediate. However, there was no such deletion with 3' pyrimidines. Our findings provide a new perspective on the role of epigenetic markers in DNA replication and could help to develop methods to identify mutation patterns associated with specific mutational signatures or spectra in cancer.