Can DNA‐Protein Crosslinking Be Induced by One‐Electron Oxidation of 8‐Oxoguanosine? A Model Study of 9‐Methyl‐8‐Oxoguanine Radical Cation With Methylamine

ABSTRACT 8‐oxoguanosine (OG) is a common form of DNA damage and is itself more susceptible to further oxidative transformations. The oxidized OG derivatives can covalently bond with nucleophilic amino acid residues, contributing to DNA–protein crosslinks (DPCs). Previous research in this context focused on the reactivity of the two‐electron oxidized OG intermediate, 2‐amino‐7,9‐dihydro‐purine‐6,8‐dione (OG OX ), toward nucleophilic addition. In contrast, the role of one‐electron oxidized OG radical cations (OG •+ ) remains unexplored. Herein, we investigate a model system using 9‐methyl‐8‐oxoguanine radical cation (9MOG •+ ) as an analogue of OG nucleoside and CH 3 NH 2 as a mimic for the lysine ε ‐amine. The reaction of 9MOG •+ with methylamine was measured across a range of kinetic energy in the gas phase by guided‐ion‐beam mass spectrometry. Density functional theory (DFT) and DLPNO‐CCSD(T) quantum chemistry computations were performed to elucidate reaction pathways and structures. Our results reveal that at low reaction energies, DPCs occur through direct nucleophilic addition, yielding C2‐ + NH 2 CH 3 [9MOG] • and C4‐ + NH 2 CH 3 [9MOG] • . At high energies, DPCs become possible between protonated [9MOG+H] + and • CH 2 NH 2 / • NHCH 3 generated from hydrogen abstraction. This work provides insights into the distinct roles of one‐ versus two‐electron oxidized OG species in DPC formation, expanding knowledge of OG lesions and their biological consequences.