Work

Crosslinking pathways, dynamics, and kinetics between guanosine and lysine following one- versus two-electron oxidation of guanosine

Year: 2025

Type: article

Abstract: DNA-protein crosslinks (DPCs) remain as a poorly understood DNA lesion. Herein, crosslinking between guanosine and lysine was explored using a model system comprising 9-methylguanine (9MG) and CH3NH2. Crosslinking was induced by one-electron oxidized 9MG•+ radical cations and doubly oxidized [9MG - HN2]+ cations, and analyzed as a function of reaction energy using an electrospray ionization tandem mass spectrometer. Experiment was augmented by dynamics simulations and kinetics modeling. Alongside the formation of X-NH2CH3[9MG]•+ (X = C2, C8) via direct addition, 8-CH2NH2[9MG + HN7]+ was discovered as a new crosslink between 9MG•+ and CH3NH2. This crosslink results from methyl-hydrogen abstraction of CH3NH2 by the N7 of 9MG•+, followed by adding •CH2NH2 to [9MG + HN7]+. Notably, crosslinking is dramatically enhanced between [9MG - HN2]+ and CH3NH2, yielding major products X-+NH2CH3[9MG - HN2] (X = N2, N3, C5, and C8, along with their proton tautomers), which form from the direct CH3NH2 addition to [9MG - HN2]+, and minor products X-CH2NH2[9MG - HN2 + HO6]+ (X = N2, N3, C5, N7, and C8), which arise from the combination of methyl-hydrogen abstraction products. This work dissected and distinguished the roles of one- versus two-electron oxidized guanosine in DPC formation, offering novel insights into oxidative DNA damage.

Source: Nucleic Acids Research

DOI: 10.1093/nar/gkaf071

Authors: May Myat Moe, Jonathan Benny, Varonica Lee, Midas Tsai, Jianbo Liu

Institutions: Queens College, CUNY, The Graduate Center, CUNY, City University of New York, LaGuardia Community College

Language: English

Topic: DNA and Nucleic Acid Chemistry

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $3,992

Funder: National Science Foundation