Longevity & AgingKey Enzyme TDG Repairs Mutagenic DNA Oxidation Damage Linked to Aging and Cancer
Oxidative DNA damage accumulates with age and drives cancer. The adenine lesion 7,8-dihydro-8-oxoadenine (oxoA) is mutagenic in human cells, yet its repair has been poorly understood. This study reveals that thymine DNA glycosylase (TDG) efficiently removes oxoA from DNA, with activity varying up to 7,300-fold depending on which base is paired opposite oxoA. The enzyme shows highest efficiency for G·oxoA pairs and lowest for T·oxoA pairs. Catalytic efficiency reflects both binding affinity and chemical reaction rate. Unlike related repair enzymes, TDG does not use acid catalysis for oxoA removal, instead stabilizing an anionic leaving group. Two active-site residues, H151 and Y152, play distinct substrate-specific roles, deepening understanding of how TDG's flexible active site handles diverse DNA lesions.
