Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.
Maurice MichelCarlos Benítez-BuelgaPatricia A CalvoBishoy M F HannaOliver MortusewiczGeoffrey MasuyerJonathan R DaviesOlov WallnerKumar SanjivJulian J AlbersSergio Castañeda-ZegarraAnn-Sofie JemthTorkild VisnesAna Sastre-PeronaAkhilesh N DandaEvert J HomanKarthick MarimuthuZhao ZhenjunCelestine N ChiAntonio SarnoElisée WiitaCatharina von NicolaiAnna J KomorVarshni RajagopalSarah MüllerEmily C HankMarek VargaEmma R ScalettiMonica PandeyStella KarstenHanne Haslene-HoxSimon LoevenichPetra MarttilaAzita RastiKirill MamonovFlorian OrtisFritz SchömbergOlga LosevaJosephine StewartNicholas D'Arcy-EvansTobias KoolmeisterMartin HenrikssonDana MichelAna de OryLucia AceroOriol CalveteMartin ScobieChristian HertweckIvan VilotijevicChristina KalderénAna OsorioRosario PeronaAlexandra StolzPål StenmarkUlrika Warpman BerglundMiguel de VegaThomas HelledayPublished in: Science (New York, N.Y.) (2022)
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.