Mass spectrometric methods for the analysis of nucleoside-protein cross-links: application to oxopropenyl-deoxyadenosine

Chemical Research in Toxicology
Sarah C ShuckLawrence J Marnett

Abstract

Electrophilic DNA adducts produced following oxidative stress can form DNA-protein cross-links (DPCs), dramatically altering genomic maintenance pathways. Complete characterization of DPCs has been hindered, in part, because of a lack of comprehensive techniques for their analysis. We have, therefore, established a proteomics approach to investigate sites of cross-link formation using N(6)-(3-oxo-1-propenyl)-2'-deoxyadenosine (OPdA), an electrophilic DNA adduct produced from oxidative stress. OPdA was reacted with albumin and reduced with NaBH4 to stabilize DPCs. Using LC-MS/MS proteomics techniques, high-resolution peptide sequence data were obtained; however, using a database searching strategy, adducted peptides were only identified in samples subjected to chemical depurination. This strategy revealed multiple oxopropenyl adenine-lysine adducts and oxopropenyl-lysine adducts with the most reactive lysines identified to be Lys256 and Lys548. Manual interrogation of the mass spectral data provided evidence of OPdA deoxynucleoside conjugates to lysines and cross-links that underwent facile collision-induced dissociation to release an unmodified peptide without subsequent fragmentation. These fragmentations precluded adduct dete...Continue Reading

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Citations

Dec 9, 2016·Chemical Research in Toxicology·James J Galligan, Lawrence J Marnett
Jul 16, 2016·Circulation Research·Kathy K GriendlingUNKNOWN American Heart Association Council on Basic Cardiovascular Sciences
Apr 26, 2019·Biometrics·Wu Wang, Ying Sun
Sep 12, 2014·Chemical Research in Toxicology·Sarah C ShuckLawrence J Marnett
Dec 4, 2021·Physical Chemistry Chemical Physics : PCCP·Linjie ZhengMathias Rapacioli

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