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

Oxidative DNA damage is recognised by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1), initiating repair. Here, we describe a small molecule (TH10785) that interacts with the Phe319 and Gly42 amino acids of OGG1, increases the enzyme activity 10-fold and generates a novel 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 ageing.European Research Council, TAROX-695376Swedish Research Council, 2015-00162, 2018-03406Ministry of Science and Innovation, Spain/10.13039/501.100011033European Regional Development Fund, BFU2017-83900-PCrafoord Foundation, 20190532Alfred Osterlund FoundationSwedish Pain Relief FoundationSwedish Cancer Society, CAN 2018/0658, CAN 2017/716Torsten and Ragnar Soderberg FoundationDr. Ake Olsson Foundation for Hematological Research, 2020-00306Thomas Helleday FoundationNTNU Enabling Technology Programme on BiotechnologyEMBO Short-Term Fellowship 9005FEBS Short-Term FellowshipScandinavian ExchangeGerman Research Foundation, 239748522Sonderforschungsbereich, 1127Leibniz AwardNorwegian Research Council, 303369Karolinska Institutet Research Foundation, 2020-02186Lars Hiertas Minne StiftelseAsociacion Espanola Contra Cancer, POSTD20042BENIInstituto de Salud Carlos III CP19/00063, PI20/00329, PI19/00640European Social FundInnovative Medicines Initiative, 875510EU's Horizon 2020 research and innovation program, Marie Sklodowska-Curie, 722729Accepte