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Oxygen Dependent Purine Lesions in Double-Stranded Oligodeoxynucleotides: Kinetic and Computational Studies Highlight the Mechanism for 5 ',8-Cyclopurine Formation

Journal article
Authors C. Chatgilialoglu
Leif A Eriksson
M. G. Krokidis
A. Masi
S. D. Wang
R. B. Zhang
Published in Journal of the American Chemical Society
Volume 142
Issue 12
Pages 5825-5833
ISSN 0002-7863
Publication year 2020
Published at Department of Chemistry and Molecular Biology
Pages 5825-5833
Language en
Links dx.doi.org/10.1021/jacs.0c00945
Keywords hydroxyl radicals, repair pathway, rate constants, c5' radicals, DNA-damage, guanine, insights, stress, model, Chemistry
Subject categories Molecular biology

Abstract

The reaction of HO center dot radical with DNA is intensively studied both mechanistically and analytically for lesions formation. Several aspects related to the reaction paths of purine moieties with the formation of 5',8-cyclopurines (cPu), 8-oxopurines (8-oxo-Pu), and their relationship are not well understood. In this study, we investigated the reaction of HO center dot radical with a 21-mer double-stranded oligodeoxynucleotide (ds-ODNs) in gamma-irradiated aqueous solutions under various oxygen concentrations and accurately quantified the six purine lesions (i.e., four cPu and two 8-oxo-Pu) by LC-MS/MS analysis using isotopomeric internal standards. In the absence of oxygen, 8-oxo-Pu lesions are only similar to 4 times more than cPu lesions. By increasing oxygen concentration, the 8-oxo-Pu and the cPu gradually increase and decrease, respectively, reaching a gap of similar to 130 times at 2.01 x 10(-4) M of O-2. Kinetic treatment of the data allows to estimate the C5' radical competition between cyclization and oxygen trapping in ds-ODNs, and lastly the rate constants of the four cyclization steps. Tailored computational studies by means of dispersion-corrected DFT calculations were performed on the CGC and TAT in their double-strand models for each cPu diastereoisomer along with the complete reaction pathways of the cyclization steps. Our findings reveal unheralded reaction mechanisms that resolve the long-standing issues with C5' radical cyclization in purine moieties of DNA sequences.

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