title: Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts.
abstract: DNA nucleobases are the prime targets for chemical modifications by endogenous and exogenous electrophiles. Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N5-substituted formamidopyrimidine (N5-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N5-substituted FAPy lesions have not been fully elucidated. To enable their structural and biological evaluation, N5-R-FAPy adducts must be site-specifically incorporated into synthetic DNA strands using phosphoramidite building blocks, which can be complicated by their unusual structural complexity. N5-R-FAPy exist as a mixture of rotamers and can undergo isomerization between α, β anomers and furanose-pyranose forms. In this Perspective, we will discuss the main types of N5-R-FAPy adducts and summarize the strategies for their synthesis and structural elucidation. We will also summarize the chemical biology studies conducted with N5-R-FAPy-containing DNA to elucidate their effects on DNA replication and to identify the mechanisms of N5-R-FAPy repair.
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Suresh S
authors.identifier: 0000-0002-0246-3362
authors.initials: SS
authors.lastname: Pujari
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Natalia
authors.identifier: 0000-0002-0621-6860
authors.initials: N
authors.lastname: Tretyakova
mesh_terms: D000818:Animals; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D004260:DNA Repair; D005559:Formamides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018736:DNA Adducts; D005559:Formamides; D009838:Oligodeoxyribonucleotides; D011743:Pyrimidines