학술논문
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
Document Type
Artikel
Author
Michel, Maurice; Benitez-Buelga, Carlos; Calvo, Patricia A; Hanna, Bishoy M F; Mortusewicz, Oliver; Masuyer, Geoffrey; Davies, Jonathan; Wallner, Olov; Sanjiv, Kumar; Albers, Julian J; Castaneda-Zegarra, Sergio; Jemth, Ann-Sofie; Visnes, Torkild; Saste-Perona, Ana; Danda, Akhilesh N; Homan, Evert J; Marimuthu, Kartrick; Zhenjun, Zhao; Chi, Celestine N; Sarno, Antonio; Wiita, Elisee; von Nicolai, Catharina; Komor, Anna J; Rajagopal, Varshni; Müller, Sarah; Hank, Emily C; Varga, Marek; Scaletti, Emma R; Pandey, Monica; Karsten, Stella; Haslene-Hox, Hanne; Loevenich, Simon; Marttila, Petra; Rasti, Azita; Mamonov, Kirill; Ortis, Florian; Schömberg, Fritz; Loseva, Olga; Stewart, Josephine; D'Arcy-Evans, Nicholas; Koolmeister, Tobias; Henriksson, Martin; Michel, Dana; de Ory, Ana; Acero, Lucia; Calvete, Oriol; Scobie, Martin; Hertweck, Christian; Vilotijevic, Ivan; Kalderén, Christina; Osorio, Ana; Perona, Rosario; Stolz, Alexandra; Stenmark, Pal; Warpman Berglund, Ulrika; de Vega, Miguel; Helleday, Thomas
Source
Science.
Subject
Language
English
ISSN
1095-9203
1095-9203
1095-9203
Abstract
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.