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Long-range oxidative damage to DNA: effects of distance and sequence.
Chem Biol. 1999 Feb; 6(2):85-97.CB

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 degrees 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.

Authors+Show Affiliations

Division of Chemistry and Chemical Engineering, California Institute ofTechnology, Pasadena 91125, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10021416

Citation

Núñez, M E., et al. "Long-range Oxidative Damage to DNA: Effects of Distance and Sequence." Chemistry & Biology, vol. 6, no. 2, 1999, pp. 85-97.
Núñez ME, Hall DB, Barton JK. Long-range oxidative damage to DNA: effects of distance and sequence. Chem Biol. 1999;6(2):85-97.
Núñez, M. E., Hall, D. B., & Barton, J. K. (1999). Long-range oxidative damage to DNA: effects of distance and sequence. Chemistry & Biology, 6(2), 85-97.
Núñez ME, Hall DB, Barton JK. Long-range Oxidative Damage to DNA: Effects of Distance and Sequence. Chem Biol. 1999;6(2):85-97. PubMed PMID: 10021416.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-range oxidative damage to DNA: effects of distance and sequence. AU - Núñez,M E, AU - Hall,D B, AU - Barton,J K, PY - 1999/2/18/pubmed PY - 1999/2/18/medline PY - 1999/2/18/entrez SP - 85 EP - 97 JF - Chemistry & biology JO - Chem. Biol. VL - 6 IS - 2 N2 - 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 degrees 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. SN - 1074-5521 UR - https://www.unboundmedicine.com/medline/citation/10021416/Long_range_oxidative_damage_to_DNA:_effects_of_distance_and_sequence_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1074-5521(99)80005-2 DB - PRIME DP - Unbound Medicine ER -