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

Núñez, Megan E. and Hall, Daniel B. and Barton, Jacqueline K. (1999) Long-range oxidative damage to DNA: Effects of distance and sequence. Chemistry and Biology, 6 (2). pp. 85-97. ISSN 1074-5521. https://resolver.caltech.edu/CaltechAUTHORS:20160330-112528546

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/S1074-5521(99)80005-2DOIArticle
http://www.sciencedirect.com/science/article/pii/S1074552199800052PublisherArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
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.
Funders:
Funding AgencyGrant Number
NIHGM49216
National Foundation for Cancer ResearchUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:base stacking; electron transfer; guanine doublets; metallointercalator; oxidative DNA damage
Issue or Number:2
Record Number:CaltechAUTHORS:20160330-112528546
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160330-112528546
Official Citation:Megan E Núñez, Daniel B Hall, Jacqueline K Barton, Long-range oxidative damage to DNA: Effects of distance and sequence, Chemistry & Biology, Volume 6, Issue 2, February 1999, Pages 85-97, ISSN 1074-5521, http://dx.doi.org/10.1016/S1074-5521(99)80005-2. (http://www.sciencedirect.com/science/article/pii/S1074552199800052)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65761
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:30 Mar 2016 21:20
Last Modified:03 Oct 2019 09:50

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