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Published February 1999 | public
Journal Article

Long-range oxidative damage to DNA: Effects of distance and sequence

Abstract

Introduction: Oxidative damage to DNA in vivo can lead to mutations and cancer. DNA damage and repair studies have not yet revealed whether permanent oxidative lesions are generated by charges migrating over long distances. Both photoexcited ^*Rh(III) and ground-state Ru(III) intercalators were previously shown to oxidize guanine bases from a remote site in oligonucleotide duplexes by DNA-mediated electron transfer. Here we examine much longer charge-transport distances and explore the sensitivity of the reaction to intervening sequences. Results: Oxidative damage was examined in a series of DNA duplexes containing a pendant intercalating photooxidant. These studies revealed a shallow dependence on distance and no dependence on the phasing orientation of the oxidant relative to the site of damage, 5′-GG-3′. The intervening DNA sequence has a significant effect on the yield of guanine oxidation, however. Oxidation through multiple 5′-TA-3′ steps is substantially diminished compared to through other base steps. We observed intraduplex guanine oxidation by tethered *Rh(III) and Ru(III) over a distance of 200 A. The distribution of oxidized guanine varied as a function of temperature between 5 and 35 °C, with an increase in the proportion of long-range damage (> 100 A) occurring at higher temperatures. Conclusions: Guanines are oxidized as a result of DNA-mediated charge transport over significant distances (e.g. 200 A). Although long-range charge transfer is dependent on distance, it appears to be modulated by intervening sequence and sequence-dependent dynamics. These discoveries hold important implications with respect to DNA damage in vivo.

Additional Information

© 1998 Elsevier Science ltd. Received 2 October 1998, Revised 16 November 1998, Accepted 17 November 1998, Available online 10 May 1999. We thank the National Institutes of Health (GM49216) and the National Foundation for Cancer Research for financial support of this research, the National Institutes of Health for a predoctoral training grant to D.B.H., and the Howard Hughes Medical Institute for a predoctoral fellowship to M.E.N. We would also like to extend our thanks to Michelle Arkin, Lee Friedman and Maureen Renta for their assistance.

Additional details

Created:
August 22, 2023
Modified:
October 18, 2023