# Mechanisms for Radiation Damage to DNA: LET Effects

> **NIH NIH R01** · OAKLAND UNIVERSITY · 2020 · $225,000

## Abstract

PROJECT SUMMARY:
 Our proposed comprehensive model of DNA radiation-induced damage describes physicochemical
events from the initial track structure and DNA ion-radical-excited state formation through hole and
electron transfer, to chemical events involving free radical processes that lead to secondary radicals
and, finally, to combination and redox processes that result in DNA damage such as base and sugar
damage, strand scission and associated base release. The overall goal of the current proposed effort is
to test several aspects this overall model, to modify it as appropriate, and thereby elucidate
fundamental mechanisms of radiation damage to DNA by radiations of varying linear energy transfer
(LET). These studies will be performed under conditions that emphasize the direct effect of radiation,
and will employ magnetic resonance spectroscopies (ESR, NMR), product analyses (HPLC, LC-
MS/MS), gamma and cyclotron heavy ion-beam irradiation, as well as theoretical modeling including
time dependent density functional theory (TD-DFT). The first aim will determine the protonation state of
the hole (guanine cation radical (G•+)) in a G-quadruplex. Subsequently, it will test the feasibility of hole
transfer process from a single guanine base to a guanine in G-quadruplexes within a DNA-oligomer as
well as the hole transfer process from a G-quadruplex to DNA base analogs of varying redox potential
such as the easily oxidized pseudoisoguanine (PIG). It will also whether G-quadruplex is an ultimate
local sink of radiation-produced electrons. These studies will test the hypotheses that the G-quadruplex,
owing to its low redox potential, will protect against radiation-induced hole and electron transfer
processes as well as excitation events and are of significance to radiation damage to telomeres. The
second aim involves the role of ion-beams in DNA damage in nucleohistone and in DNA and will test
the hypothesis that the yield of sugar radicals from LEE and excited state processes increase as LET
increases along the beam path. C3’•dephos will be used as a marker for LEE-induced processes along
the beam path. The ratio of purine to pyrimidine base release will be used as a marker for excitation-
induced strand breaks. We will test the hypotheses that at the Bragg peak, where fewer radicals are
stabilized in nucleohistone or in DNA owing to the ion-radical recombination events, changes will occur
in the individual DNA damage product yields and their nature from that found in the ion-beam LET
plateau region. The third aim will employ theoretical calculations to further test and confirm molecular
mechanisms proposed in each of the above-mentioned aims. In addition, several hypotheses will be
tested. The most important is that redox properties calculated with DFT can predict the fate of DNA-
radical intermediates. This aim directly aids Aim 1. These efforts will allow us to establish new insights
into the fundamental radiation-induced physicochemical processes ...

## Key facts

- **NIH application ID:** 9867711
- **Project number:** 5R01CA045424-32
- **Recipient organization:** OAKLAND UNIVERSITY
- **Principal Investigator:** MICHAEL Douglas SEVILLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,000
- **Award type:** 5
- **Project period:** 1987-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867711

## Citation

> US National Institutes of Health, RePORTER application 9867711, Mechanisms for Radiation Damage to DNA: LET Effects (5R01CA045424-32). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9867711. Licensed CC0.

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