# Studies of Chemically Labile Alkylation Damage in DNA > **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $343,610 ## Abstract ABSTRACT Alkylation DNA damage caused by alkylating agents promotes mutations and cancer development. Guanine N7 is targeted by a wide range of alkylating mutagens, carcinogens, and anticancer agents, producing the cationic N7-alkylguanine (N7-alkylG) adducts as major lesions. These lesions have half-lives of several hours to days in DNA and thus can affect DNA replication and transcription. The positively charged N7-alkylG lesions can also undergo further modification to generate secondary lesions such as alkyl-formamidopyrimidine (alkyl-FapyG) adducts. The recognition, repair, and mutagenesis mechanisms of many mutagen/carcinogen-induced N7- alkylG and alkyl-FapyG lesions, except for a few lesions such as N7-aflatoxin B1-G and aflatoxin B1-FapyG adducts, remain poorly characterized, thereby precluding a complete understanding of the contribution of these major lesions to mutations and cancer development. For example, the mutagenic properties of the predominant N7-alkylG adducts produced by the cancer-promoting styrene oxide are unknown. This knowledge gap has been due in part to the technical difficulty in preparing a site-specific N7-alkylG- and alkyl-FapyG-containing DNA, which is ascribed to the rapid depurination of N7-alkylG nucleosides and the facile isomerization of alkyl- FapyG during solid-phase DNA synthesis. To overcome the stability issue of N7-alkylG nucleosides, we have developed a 2’-fluorine technology that prevents spontaneous depurination by increasing the stability of N7- alkylG nucleosides. To solve the isomerization problem of alkyl-FapyG, we have taken a post-synthetic approach that produces alkyl-FapyG-containing DNA from N7-alkylG-containing DNA. Our preliminary studies show that guanine N7 alkylation can influence base-pairing properties by facilitating the formation of the rare enol tautomer, syn base conformation, and/or intercalation. Our central hypothesis is that N7-alkylG and alkyl- FapyG adducts promote mutations and cancer development by altering the base-pairing properties of the damaged guanine. Our long-term research goal is to elucidate the biological impacts of chemically labile alkylation damages and their secondary lesions using innovative approaches such as the 2’-F chemistry, the polβ host-guest-complex system, and post-synthetic DNA modification. The objective is to dissect the biological consequences of N7-alkylG and alkyl-FapyG lesions induced by potent alkylating mutagens and anticancer agents such as nicotine-specific nitrosamine, styrene oxide, nitrogen mustards, and N-methylbenzyl nitrosamine. To accomplish this objective, we will characterize the base-pairing properties and the recognition, mutagenesis, and repair mechanisms of N7-alkylG and alkyl-FapyG adducts using combined tools of synthetic, biochemical, structural biology, and cellular approaches. The successful execution of the proposed programs will greatly advance our knowledge of the impact of carcinogen/drug-induced N7-alkylG and alkyl... ## Key facts - **NIH application ID:** 10906097 - **Project number:** 5R01ES034781-02 - **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN - **Principal Investigator:** Seongmin Lee - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $343,610 - **Award type:** 5 - **Project period:** 2023-08-12 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10906097 ## Citation > US National Institutes of Health, RePORTER application 10906097, Studies of Chemically Labile Alkylation Damage in DNA (5R01ES034781-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10906097. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*