Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. Description Teaching an enzyme a new trick Small molecules that activate enzymes commonly operate using allosteric control. Michel et al. describe the mode of action of a small-molecule activator that binds to the active site of 8-oxo guanine DNA glycosylase 1 (OGG1) and catalyzes a biochemical reaction not found in the naïve protein. The molecule enables the protein to completely cleave the damaged DNA strand, which results in an overall increased repair of oxidative DNA damage. The underlying creation of a new repair pathway has potential medical application in diseases related to oxidative DNA damage. —DJ A small-molecule activator of a DNA glycolase enzyme generates a new enzymatic function and increases oxidative DNA damage repair.