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

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 CH₃NH₂ 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-⁺NH₂CH₃[9MOG]^• and C4-⁺NH₂CH₃[9MOG]^•. At high energies, DPCs become possible between protonated [9MOG+H]⁺ and ^•CH₂NH₂/^•NHCH₃ 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.