Abstract
Purpose
One outcome of DNA damage from hydroxyl radical generated by ionizing radiation (IR) or by the Fenton reaction is oxidation of the nucleobases, especially guanine (G). While 8-oxo-7,8-dihydroguanine (OG) is a commonly studied oxidized lesion, several others are formed in high abundance, including 5-carboxamido-5-formamido-2-iminohydantoin (2Ih), a prevalent product in in vitro chemistry that is challenging to study from cellular sources. In this short review, we have a goal of explaining new insights into hydroxyl radical-induced oxidation chemistry of G in DNA and comparing it to endogenous DNA damage, as well as commenting on the biological outcomes of DNA base damage.
Conclusions
Pathways of oxidation of G are discussed and a comparison is made between IR (hydroxyl radical chemistry) and endogenous oxidative stress that largely forms carbonate radical anion as a reactive intermediate. These pathways overlap with the formation of OG and 2Ih, but other guanine-derived lesions are more pathway specific. The biological consequences of guanine oxidation include both mutagenesis and epigenetics; a new mechanism of gene regulation via the base excision repair pathway is described for OG, whereas the impact of IR in forming guanine modifications may be to confound this process in addition to introduction of mutagenic sites.
Acknowledgements
We thank many coworkers and collaborators over the years for experimental work and critical insights. In particular, we thank the nine women mentioned in this paper for their inspirational accomplishments in the field. Work in our laboratory was funded by the U.S. National Institutes of Health via grants R01 CA090689 and R01 GM129267.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
Aaron M. Fleming
Aaron M. Fleming, PhD, is a Research Associate Professor of Chemistry at the University of Utah.
Cynthia J. Burrows
Cynthia J. Burrows, PhD, is Distinguished Professor of Chemistry and Thatcher Presidential Chair of Biological Chemistry at the University of Utah.