| Literature DB >> 35737787 |
Maurice Michel1, Carlos Benítez-Buelga1,2, Patricia A Calvo3, Bishoy M F Hanna1, Oliver Mortusewicz1, Geoffrey Masuyer4,5, Jonathan Davies5, Olov Wallner1, Kumar Sanjiv1, Julian J Albers1, Sergio Castañeda-Zegarra1,6, Ann-Sofie Jemth1, Torkild Visnes7, Ana Sastre-Perona8, Akhilesh N Danda1, Evert J Homan1, Karthick Marimuthu1, Zhao Zhenjun1, Celestine N Chi9, Antonio Sarno10, Elisée Wiita1, Catharina von Nicolai1, Anna J Komor11, Varshni Rajagopal1, Sarah Müller1, Emily C Hank1, Marek Varga1, Emma R Scaletti5,12, Monica Pandey1,13, Stella Karsten1, Hanne Haslene-Hox7, Simon Loevenich7, Petra Marttila1, Azita Rasti1, Kirill Mamonov1, Florian Ortis1, Fritz Schömberg14, Olga Loseva1, Josephine Stewart1, Nicholas D'Arcy-Evans1, Tobias Koolmeister1, Martin Henriksson1, Dana Michel15, Ana de Ory16, Lucia Acero8, Oriol Calvete17, Martin Scobie1, Christian Hertweck11,18, Ivan Vilotijevic14, Christina Kalderén1, Ana Osorio17,19, Rosario Perona2,19, Alexandra Stolz20, Pål Stenmark5,12, Ulrika Warpman Berglund1, Miguel de Vega3, Thomas Helleday1,13.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2022 PMID： 35737787 DOI： 10.1126/science.abf8980
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728