Michael Sevilla

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.

Recent Publications

Ma, J.; Kumar, A.; Muroya, Y.; Yamashita, S.; Sakurai, T.; Denisov, S. A.; Sevilla, M. D.; Adhikary, A.; Seki, S.; Mostafavi, M. Quasi-free electron attachment to nucleoside in solution: excited anion radical formation and its dissociation. Nature Communications, 2019, 10, article number: 102, pp 1-7, https://www.nature.com/collections/wtpqpqpgwd.

Ma, J.; Marignier, J-L.; Pernot, P.; Houée-Levin, C.; Kumar, A.; Sevilla, M. D.; Adhikary, A.; Mostafavi, M., Direct Observation of the Oxidation of DNA Bases by Phosphate Radical Formed under Radiation: A Model of Backbone-to- base Hole Transfer, Phys. Chem. Chem. Phys., 2018, 20, 14927 – 14937.

Anil Kumar and Michael D. Sevilla, SOMO-HOMO Level Inversion in Biologically Important Radicals J. Phys. Chem. B, 2018, 122, 98-105.

Liwei Zheng, Lu Lin, Ke Qu, Amitava Adhikary , Michael D. Sevilla‡ , and Marc M. Greenberg, Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines   Org. Lett., Article 2017, 19 (23), pp 6444–6447.

Anil Kumar and Michael D. Sevilla, J. Cytosine Iminyl Radical (cytN•) Formation via Electron-Induced Debromination of 5-Bromocytosine: A DFT and Gaussian 4 Study, Phys. Chem. A, 2017, 121 (25), pp 4825–4829.

Banyasz, A.; Tiia-Maaria,  K.; Muñoz-Losa, A.; Rishi, S.; Adhikary, A.; Sevilla, M. D.; Martinez-Fernandez, L.; Improta, R.; Markovitsi, D. UV-induced adenine radicals induced in DNA A tracts: spectral and dynamical characterization (2016). J. Phys. Chem. Lett., 7, 3949 − 3953.

Sevilla, M. D., Becker, D., Kumar, A., Adhikary, A. (2016)  Radiation-Induced Free Radical Mechanisms in DNA. Invited Review (special issue, Rad. Chem. Biomolecules (M. Spotheim-Maurizot, L. Wojnarovits  (Eds.)), Radiat. Phys. Chem., 128, 60 - 74.

Michael D. Sevilla, David Becker, Anil Kumar, and Amitava Adhikary, Gamma and Ion-Beam Irradiation of DNA: Free Radical Mechanisms, Electron Effects, and Radiation Chemical Track Structure , Rad. Phys. and Chem..vol 128, 60-74, 2016. 

Anil Kumar, Amitava Adhikary, Lance Shamoun, and Michael D. Sevilla, Do Solvated Electrons (e_aq–) Reduce DNA Bases? A Gaussian 4 and Density Functional Theory- Molecular Dynamics Study, J. Phys. Chem. B, 2016, 120 (9), pp 2115–2123

Kumar, Anil; Walker, Jonathan; Bartels, David; Sevilla, Michael, A Simple ab initio Model for the Hydrated Electron that Matches Experiment, J. Phys. Chem. A, 2015, 119 (34), 9148–9159.

Amitava Adhikary, Anil Kumar, Casandra T. Bishop, Tyler J. Wiegand, Ragda M Hindi, Ananya Adhikary, and Michael D. Sevilla, π to σ Radical Tautomerization in One-Electron Oxidized 1-Methylcytosine and its Analogs J. Phys. Chem. B, 2015, 119 (35), pp 11496–11505.

Recent Review Articles

Kumar A., Sevilla M.D.  Low-Energy Electron (LEE)-Induced DNA Damage: Theoretical Approaches to Modeling Experiment. In: Leszczynski J., Kaczmarek-Kedziera A., Puzyn T., G. Papadopoulos M., Reis H., K. Shukla M. (eds) Handbook of Computational Chemistry. Springer, 2017.

A. Kumar and M. D. Sevilla, Low Energy Electron (LEE) Induced DNA Damage: Theoretical Approaches to Modeling Experiment,  Handbook of Computational Chemistry Volume IV: Applications – Biomolecules.”  Manoj Shukla and Jerzy Leszczynski, Eds, Springer,  2015.

 Adhikary, A., Becker, D., and Sevilla, M. D.  Chapter 8. Electron spin resonance of radicals in irradiated DNA. In Applications of EPR in radiation research (A. Lund, M. Shiotani (Eds.)),  Springer-Verlag, Berlin, Heidelberg, 299 – 352.(2014) http://www.springer.com/chemistry/book/978-3-319-09215-7