The goal of this research is to elucidate fundamental mechanisms of radiation damage to DNA by radiations of varying linear energy transfer (LET). Our comprehensive model for DNA radiation damage that describes events from the initial formation of DNA ion radicals and excited states, to hole and electron transfer, to sugar radical formation and finally to molecular products will be tested at each step to clarify the fundamental processes resulting in DNA radiation damage. These studies, which are performed under conditions that emphasize the direct effect of radiation, will employ magnetic resonance spectroscopies, density functional theory and product analysis techniques as well as gamma and cyclotron heavy ion beam irradiations. There are three aims:
The first aim will address several of the major unanswered questions in DNA radiation damage induced by holes.
This aim will employ specifically C-8 deuterium labeled defined sequence oligos to exploit a recent breakthrough in our laboratory that allows us to distinguish a hole (cation radical) at a C-8 deuterium labeled purine base (guanine or adenine) from an unlabeled site. We have also found that the C-8 labeling allows the distinction of the guanine and adenine cation radicals from their deprotonated forms. With these developments we will find: a. the base sequence dependence of hole localization, b. the protonation states of guanine and adenine cation radicals at specific sites in dsDNA, c. the extent of base-to- base versus base-to-sugar transfer on hole excitation.
Our second aim will identify radicals formed and track structure as a function of LET in ion beam irradiated DNA. We will identify radicals via ESR spectroscopy and ascertain their spatial distribution and clustering as a function of the LET of the radiation along the radiation track. Especially important will be a study of the LET dependence of recently discovered prompt strand break radicals that result from cleavage of the sugar phosphate backbone. The nature of the radical formation and clustering in the track core is pertinent to understanding the formation of the most important lesion in DNA the unrepairable multiply damaged site.
Our final aim will employ theoretical calculations to further test and confirm molecular mechanisms proposed in the above studies. Especially significant will be treatment by TD- DFT theory of excited states of base ion radicals which are now implicated in DNA strand breaks and become more significant as the LET of the radiation increases. We believe this effort will allow us to establish new insights into fundamental radiation processes important for biomedical research.

Public Health Relevance

The goal of this research is to develop a comprehensive model of DNA radiation damage by elucidating fundamental mechanisms of damage to DNA by radiations of varying linear energy transfer (LET). Our model for DNA radiation damage that describes events from the initial formation of DNA ion radicals and excited states, to hole and electron transfer, to sugar radical formation and finally to molecular products will be tested at each step to illuminate the fundamental processes resulting in DNA radiation damage. These studies, which are performed under conditions that emphasize the direct effect of radiation, will employ gamma and cyclotron heavy ion beam irradiations, magnetic resonance spectroscopies, density functional theory and product analysis techniques and will address major unanswered questions in DNA radiation damage important to biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045424-23
Application #
7798170
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
1987-07-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
23
Fiscal Year
2010
Total Cost
$209,971
Indirect Cost
Name
Oakland University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041808262
City
Rochester
State
MI
Country
United States
Zip Code
48309
Kumar, Anil; Sevilla, Michael D (2017) Cytosine Iminyl Radical (cytN•) Formation via Electron-Induced Debromination of 5-Bromocytosine: A DFT and Gaussian 4 Study. J Phys Chem A 121:4825-4829
Mudgal, Mukesh; Rishi, Sunny; Lumpuy, Daniel A et al. (2017) Prehydrated One-Electron Attachment to Azido-Modified Pentofuranoses: Aminyl Radical Formation, Rapid H-Atom Transfer, and Subsequent Ring Opening. J Phys Chem B 121:4968-4980
Ma, Jun; Wang, Furong; Denisov, Sergey A et al. (2017) Reactivity of prehydrated electrons toward nucleobases and nucleotides in aqueous solution. Sci Adv 3:e1701669
Barkam, Swetha; Ortiz, Julian; Saraf, Shashank et al. (2017) Modulating the Catalytic Activity of Cerium Oxide Nanoparticles with the Anion of the Precursor Salt. J Phys Chem C Nanomater Interfaces 121:20039-20050
Zheng, Liwei; Lin, Lu; Qu, Ke et al. (2017) Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines. Org Lett 19:6444-6447
Banyasz, Akos; Ketola, Tiia-Maaria; Muñoz-Losa, Aurora et al. (2016) UV-Induced Adenine Radicals Induced in DNA A-Tracts: Spectral and Dynamical Characterization. J Phys Chem Lett 7:3949-3953
Sevilla, Michael D; Becker, David; Kumar, Anil et al. (2016) Gamma and Ion-Beam Irradiation of DNA: Free Radical Mechanisms, Electron Effects, and Radiation Chemical Track Structure. Radiat Phys Chem Oxf Engl 1993 128:60-74
Kumar, Anil; Adhikary, Amitava; Shamoun, Lance et al. (2016) Do Solvated Electrons (e(aq)?) Reduce DNA Bases? A Gaussian 4 and Density Functional Theory-Molecular Dynamics Study. J Phys Chem B 120:2115-23
Sevilla, Michael D; Kumar, Anil; Adhikary, Amitava (2016) Comment on ""Proton Transfer of Guanine Radical Cations Studied by Time-Resolved Resonance Raman Spectroscopy Combined with Pulse Radiolysis"". J Phys Chem B 120:2984-6; discussion 2987-9
Zdrowowicz, Magdalena; Chomicz, Lidia; ?yndul, Micha? et al. (2015) 5-Thiocyanato-2'-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization. Phys Chem Chem Phys 17:16907-16

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