Independent Generation and Time-Resolved Detection of 2′-Deoxyguanosin-N2-yl Radicals

Liwei Zheng; Xiaojuan Dai; Hongmei Su; Marc M. Greenberg

doi:10.1002/anie.202005300

Independent Generation and Time-Resolved Detection of 2′-Deoxyguanosin-N2-yl Radicals

Liwei Zheng, Xiaojuan Dai, Hongmei Su, Marc M. Greenberg

Krieger School of Arts and Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO^.) has long been believed to react with 2′-deoxyguanosine (dG) generating 2′-deoxyguanosin-N1-yl radical (dG(N1-H)^.) via addition to the nucleobase π-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO^. with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2′-deoxyguanosin-N2-yl radical (dG(N2-H)^.) formed was proposed to rapidly tautomerize to dG(N1-H)^.. We report the first independent generation of dG(N2-H)^. in high yield via photolysis of 1. dG(N2-H)^. is directly observed upon nanosecond laser flash photolysis (LFP) of 1. The absorption spectrum of dG(N2-H)^. is corroborated by DFT studies, and anti- and syn-dG(N2-H)^. are resolved for the first time. The LFP experiments showed no evidence for tautomerization of dG(N2-H)^. to dG(N1-H)^. within hundreds of microseconds. This observation suggests that the generation of dG(N1-H)^. via dG(N2-H)^. following hydrogen atom abstraction from dG is unlikely to be a major pathway when HO^. reacts with dG.

Original language	English (US)
Pages (from-to)	13406-13413
Number of pages	8
Journal	Angewandte Chemie - International Edition
Volume	59
Issue number	32
DOIs	https://doi.org/10.1002/anie.202005300
State	Published - Aug 3 2020

Keywords

DNA
guanine oxidation
laser flash photolysis
oxidative stress
radicals

ASJC Scopus subject areas

Catalysis
General Chemistry

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10.1002/anie.202005300

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@article{7928af2fdef1420489eccdee606806bc,

title = "Independent Generation and Time-Resolved Detection of 2′-Deoxyguanosin-N2-yl Radicals",

abstract = "Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO.) has long been believed to react with 2′-deoxyguanosine (dG) generating 2′-deoxyguanosin-N1-yl radical (dG(N1-H).) via addition to the nucleobase π-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO. with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2′-deoxyguanosin-N2-yl radical (dG(N2-H).) formed was proposed to rapidly tautomerize to dG(N1-H).. We report the first independent generation of dG(N2-H). in high yield via photolysis of 1. dG(N2-H). is directly observed upon nanosecond laser flash photolysis (LFP) of 1. The absorption spectrum of dG(N2-H). is corroborated by DFT studies, and anti- and syn-dG(N2-H). are resolved for the first time. The LFP experiments showed no evidence for tautomerization of dG(N2-H). to dG(N1-H). within hundreds of microseconds. This observation suggests that the generation of dG(N1-H). via dG(N2-H). following hydrogen atom abstraction from dG is unlikely to be a major pathway when HO. reacts with dG.",

keywords = "DNA, guanine oxidation, laser flash photolysis, oxidative stress, radicals",

author = "Liwei Zheng and Xiaojuan Dai and Hongmei Su and Greenberg, {Marc M.}",

note = "Funding Information: We are grateful for support from the National Institute of General Medical Sciences (GM‐054996 and GM‐131736). H.S. thanks the funding support from the National Natural Science Foundation of China (21933005, 21727803 and 21425313). We thank Amit Adhikary and Michael Sevilla for helpful discussions. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

year = "2020",

month = aug,

day = "3",

doi = "10.1002/anie.202005300",

language = "English (US)",

volume = "59",

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T1 - Independent Generation and Time-Resolved Detection of 2′-Deoxyguanosin-N2-yl Radicals

AU - Zheng, Liwei

AU - Dai, Xiaojuan

AU - Su, Hongmei

AU - Greenberg, Marc M.

N1 - Funding Information: We are grateful for support from the National Institute of General Medical Sciences (GM‐054996 and GM‐131736). H.S. thanks the funding support from the National Natural Science Foundation of China (21933005, 21727803 and 21425313). We thank Amit Adhikary and Michael Sevilla for helpful discussions. Publisher Copyright: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2020/8/3

Y1 - 2020/8/3

N2 - Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO.) has long been believed to react with 2′-deoxyguanosine (dG) generating 2′-deoxyguanosin-N1-yl radical (dG(N1-H).) via addition to the nucleobase π-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO. with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2′-deoxyguanosin-N2-yl radical (dG(N2-H).) formed was proposed to rapidly tautomerize to dG(N1-H).. We report the first independent generation of dG(N2-H). in high yield via photolysis of 1. dG(N2-H). is directly observed upon nanosecond laser flash photolysis (LFP) of 1. The absorption spectrum of dG(N2-H). is corroborated by DFT studies, and anti- and syn-dG(N2-H). are resolved for the first time. The LFP experiments showed no evidence for tautomerization of dG(N2-H). to dG(N1-H). within hundreds of microseconds. This observation suggests that the generation of dG(N1-H). via dG(N2-H). following hydrogen atom abstraction from dG is unlikely to be a major pathway when HO. reacts with dG.

AB - Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO.) has long been believed to react with 2′-deoxyguanosine (dG) generating 2′-deoxyguanosin-N1-yl radical (dG(N1-H).) via addition to the nucleobase π-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO. with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2′-deoxyguanosin-N2-yl radical (dG(N2-H).) formed was proposed to rapidly tautomerize to dG(N1-H).. We report the first independent generation of dG(N2-H). in high yield via photolysis of 1. dG(N2-H). is directly observed upon nanosecond laser flash photolysis (LFP) of 1. The absorption spectrum of dG(N2-H). is corroborated by DFT studies, and anti- and syn-dG(N2-H). are resolved for the first time. The LFP experiments showed no evidence for tautomerization of dG(N2-H). to dG(N1-H). within hundreds of microseconds. This observation suggests that the generation of dG(N1-H). via dG(N2-H). following hydrogen atom abstraction from dG is unlikely to be a major pathway when HO. reacts with dG.

KW - DNA

KW - guanine oxidation

KW - laser flash photolysis

KW - oxidative stress

KW - radicals

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JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 32

ER -

Independent Generation and Time-Resolved Detection of 2′-Deoxyguanosin-N2-yl Radicals

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Keywords

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