Title: Distinguished Professor
Office: 248 Science and Engineering Building
Phone: (248) 370-2328
Fax: (248) 370-2321
Radiation, Free Radicals and DNA Damage
The Sevilla group’s research interests are the chemistry of free radical species produced by the high energy irradiation of DNA by gamma irradiation and ion beams. Both radiations are employed in treatment of cancer. Ion beams are increasingly of interest as they can be directed to the tumor and will stop in the tumor. The principal biological effect of radiation on a cell is caused by the direct interaction of radiation with DNA or molecules immediately surrounding the DNA which transmit the radiation damage to the DNA. Radiation induces ionizations, free electrons, excitations in DNA which decay to a variety of free radical intermediates. These reactive species create damages on DNA bases and the sugar phosphate backbone that may lead to cellular death or mutation.
Views of a B-DNA dodecamer.
Recent efforts have looked into the production of sugar radicals in DNA by high energy irradiation. These species are of critical importance to the subsequent biological damage and as a consequence quantitation of the numbers of sugar radicals and their identity gives important mechanistic information. Work in this lab has found that about 10% of all radicals produced are on the sugar phosphate backbone for gamma rays but as much as 30% of radicals are on the sugar phosphate backbone for ion beam irradiated DNA. This lead to the hypothesis that excited states of the DNA base cation radicals may lead to damage to the sugar portion of DNA. A series of recent papers have shown this is indeed the case. These efforts have identified the C1’, C3’ and C5’ sites on the sugar as those that are most prone to damage by this mechanism. Sugar radicals result in DNA strand breaks and loss of DNA biological function.
The radiation produced guanine cation radical undergoes intra-base pair proton transfer and is localized to one base in DNA.
Electrons produced by radiation can also be damaging entities while they have kinetic energy. Such species are called low energy electrons and have been recently shown to fragment the DNA strand to produce single and even double strand breaks. Ab initio molecular orbital calculations have been recently employed to aid our understanding of the chemistry and structure of radiation produced species. For example, the Sevilla group is currently using time dependent density functional theory (TD-DFT) in the investigation of the role of excited states in the mechanisms of radiation damage. The major finding is that electronic excited states when combined with DNA ion radicals lead to the formation of strand breaks.
Low energy electrons (LEEs) interact with a DNA model system to create a variety of excited states. Dissociative (s*) states are accessible by LEEs with energy < 4 eV and cause facile strand break formation.
Prototropic equilibria in DNA containing one-electron oxidized GC: intra-duplex vs. duplex to solvent deprotonation,
Amitava Adhikary, Anil Kumar, Shawn A. Munafo, Deepti Khanduri and Michael D. Sevilla, Phys. Chem. Chem. Phys
.,12, 5363-5368, 2010.
Formation of Aminyl Radicals on Electron Attachment to AZT: Abstraction from the Sugar Phosphate Backbone versus One-Electron Oxidation of Guanine
Amitava Adhikary, Deepti Khanduri, Venkata Pottiboyina, Cory T. Rice and Michael D. Sevilla, J. Phys. Chem. B
, 114, 9289–9299, 2010.
Highly Oxidizing Excited States of One-Electron-Oxidized Guanine in DNA: Wavelength and pH Dependence,
Deepti Khanduri, Amitava Adhikary, and Michael D. Sevilla, J. Am. Chem. Soc.
, 2011, 133 (12), 4527–4537.
DFT Studies of the Extent of Hole Delocalization in One-electron Oxidized Adenine and Guanine base Stacks,
Anil Kumar and Michael D. Sevilla*, J. Phys. Chem. B
, 2011, 115 (17), 4990–5000.
Hydroxyl Radical (OH•) Reaction with Guanine in an Aqueous Environment: A DFT Study, Anil Kumar, Venkata Pottiboyina and Michael D. Sevilla, J. Phys. Chem. B, 2011, 115 (50), 15129–15137.
Formation of N-N Cross-Links in DNA by Reaction of Radiation Produced DNA Base Pair Diradicals: A DFT Study, Venkata Pottiboyina, Anil Kumar and Michael D. Sevilla, J. Phys. Chem. B, 2011, 115 (50), 15090–15097.
Radicals Formed in N-Acetyl-Proline by Electron Attachment: ESR Spectroscopy and Computational Studies, Jeanette F. Kheir, Lidia Chomicz, Janusz Rak, Kit H. Bowen and Michael D. Sevilla, J. Phys. Chem. B, 2011 (49),115, 14846-14851.
Direct Strand Scission in Double Stranded RNA via a C5-Pyrimidine Radical, Marino J. E. Resendiz, Venkata Pottiboyina, Michael D. Sevilla, and Marc M. Greenber, J. Am. Chem. Soc., 2012, 134 (8), pp 3917–3924.
Direct Formation of the C5′-Radical in the Sugar–Phosphate Backbone of DNA by High- Energy Radiation, Amitava Adhikary, David Becker, Brian J. Palmer, Alicia N. Heizer, and Michael D. Sevilla, J. Phys. Chem. B, 2012, 116 (20), pp 5900–5906.
One-Electron Oxidation of Neutral Sugar Radicals of 2′-Deoxyguanosine and 2′-Deoxythymidine: A Density Functional Theory (DFT) Study, Anil Kumar, Venkata Pottiboyina, and Michael D. Sevilla, J. Phys. Chem. B, 2012, 116 (31), pp 9409–9416.
Recent Review Articles
A. Kumar and M. D. Sevilla, Low Energy Electron (LEE) Induced DNA Damage: Theoretical Approaches to Modeling Experiment, Handbook of Computational Chemistry Volume III: Applications – Biomolecules. Manoj Shukla and Jerzy Leszczynski, Eds, Springer, 2012.
Adhikary, A., Kumar, A., Becker, D., and Sevilla, M. D., Theory and ESR spectral studies of DNA-radicals. In Encyclopedia of Radicals in Chemistry, Biology and Materials. (C. Chatgilialoglu, A. Struder (Eds.)), John Wiley & Sons, Ltd., The Atrium, Southern Gate, Chichester, West Sussex, Vol 3 Chapter 47, 2012.