# Synthesis, structure and biological effects of carcinogen/drug-induced bulky, intercalatable N7-alkylguanine lesions

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $276,200

## Abstract

Covalent modification of DNA by alkylating mutagens and carcinogens is closely associated with cancer
development. A wide variety of alkylating agents are known to attack DNA to produce N7-alkylguanine (N7-
alkylG) and alkyl formamidopyrimidine (alkyl-FapyG) lesions. Despite the major advances in the
characterization of chemical, biochemical, and/or mutagenic properties of the lesions, our molecular-level
understanding of structural and biological effects of carcinogen/drug-induced bulky intercalatable N7-alkylG
and alkyl-FapyG adducts is still limited, except for a few lesions such as aflatoxin B1-N7G adducts. This
knowledge gap had been due in part to a technical limitation in generating sufficient quantities of DNA
containing site-specific incorporated N7-alkylG; although N7-alkylG lesions in duplex DNA have half-lives of
several hours to days, the lesions in nucleosides are chemically extremely unstable to rapidly undergo
spontaneous depurination, thereby precluding the use of the solid-phase method for the synthesis of N7-
alkylG-containing DNA. We previously developed a transition-state destabilization strategy to solve the
chemical instability problem and reported the first crystal structure of an N7-alkylG-containing DNA. Our
central hypothesis of the proposed research is that bulky, intercalatable N7-alkylG and alkyl-FapyG lesions
affect DNA structure and biological processes including DNA replication and mutagenesis. Our long-term
research goal is to elucidate the structural and biological effects of carcinogen/drug-induced N7-alkylG and
N3-alkyladenine lesions. The objectives here are to elucidate the impacts of N7-alkylG and alkyl-FapyG
lesions on DNA structure, replication and mutagenesis and to dissect the DNA repair mechanism of the
lesions. To accomplish this objective, we propose synthesis, structure determination, and biochemical
evaluation of N7-alkylG and alkyl-FapyG lesions that are induced by potent carcinogens/drugs including N-
methylbenzyl nitrosamine, safrole, ptaquiloside, acridine half-mustard ICR-191, nitrogen half-mustard, and a
platinum-based “alkylating-like” agent. As a next step for achieving our long-term goals, we have designed
three Specific Aims that are 1) Evaluating the impact of the N7-alkylG and alkyl-FapyG lesions on the
structure and stability of duplex DNA; 2) Elucidating the mutagenesis mechanisms of the lesions; and 3)
Delineating the DNA repair mechanism for the lesions. Our expectation is that the accomplishment of the
proposed research would advance our molecular-level understanding of the impact of intercalatable N7-alkylG
and alkyl-FapyG adducts on DNA structure, replication and mutagenesis and the repair mechanism of the
lesions, thereby providing new insights into the etiology of alkylation-induced mutagenesis and carcinogenesis.
In addition, crystal structures of N7-alkylG-containing DNA would facilitate a structure-based design and
development of novel alkylating agents that can alter DNA st...

## Key facts

- **NIH application ID:** 10233991
- **Project number:** 5R01ES026676-05
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Seongmin Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $276,200
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233991

## Citation

> US National Institutes of Health, RePORTER application 10233991, Synthesis, structure and biological effects of carcinogen/drug-induced bulky, intercalatable N7-alkylguanine lesions (5R01ES026676-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10233991. Licensed CC0.

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