Chemical Biology of N5-substituted formamidopyrimidine DNA adducts

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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-RFAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1 have 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 sitespecifically 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.

Original languageEnglish (US)
Pages (from-to)434-452
Number of pages19
JournalChemical research in toxicology
Volume30
Issue number1
DOIs
StatePublished - Jan 17 2017

Bibliographical note

Funding Information:
*Masonic Cancer Center, University of Minnesota, 2231 Sixth Street SE, 2-147 CCRB, Minneapolis, MN 55455, USA. Phone: 612-626-3432. Fax: 612-624-3869. E-mail: trety001@umn.edu. ORCID Suresh S. Pujari: 0000-0002-0246-3362 Natalia Tretyakova: 0000-0002-0621-6860 Funding Funding for this research was provided by grants from the National Cancer Institute (CA1006700), the National Institute of Environmental Health Sciences (ES023350), and University of Minnesota College of Pharmacy. Notes The authors declare no competing financial interest. Biographies

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