Glyoxalase 1 Regulates Methylglyoxal-Derived Nucleic Acid Adduct Burden

Increased metabolic stress associated with diabetes and cancer increases the level of reactive dicarbonyl molecules that covalently modify nucleic acids. Methylglyoxal (MG), one of the most abundant endogenous dicarbonyl electrophiles, reacts with guanine bases in DNA and RNA to form covalent adducts that compromise genomic and RNA integrity. The primary MG-derived adduct in DNA is N2-carboxyethyl deoxyguanosine (CEdG), and in RNA, it is N2-carboxyethyl guanosine (CEG). CEdG is mutagenic, while CEG decreases mRNA stability and impairs translation. To prevent adduct formation, cells utilize the glyoxalase pathway, which is the primary pathway for detoxifying MG. Glyoxalase 1 (GLO1) is the first enzyme in this pathway. While GLO1 is frequently dysregulated in metabolic disease and cancer, its role in regulating MG-induced nucleic acid adduct burden and the downstream functional consequences remains incompletely defined. Here, we demonstrate that the genetic ablation of GLO1 significantly increases the accumulation of MG-derived DNA and RNA adducts. We found that an elevated CEdG adduct burden is associated with increased DNA strand breaks, whereas increased CEG modifications are associated with reduced translational efficiency. These findings establish GLO1 as a critical regulator of the endogenous nucleic acid modification burden and mechanistically link metabolic stress-derived chemical lesions to genome instability and translational dysfunction.