瑞典卡罗林斯卡医学院Thomas Helleday和Maurice Michel研究组合作发现，小分子激活8-氧鸟嘌呤 (8-oxoG) DNA 糖基化酶 1 (OGG1)可获得新的功能，从而促进DNA氧化损伤修复。该研究于2022年6月24日发表于国际一流学术期刊《科学》杂志上。
他们描述了一个小分子 (TH10785)，它与 OGG1 的苯丙氨酸 319 和甘氨酸 42 氨基酸相互作用，将酶活性提高 10 倍，并产生以前未描述的 β,δ-裂解酶功能。TH10785 控制由其分子结构内的氮碱介导的催化活性。在细胞中，TH10785 增加 OGG1 对氧化性 DNA 损伤的募集和修复。这改变了修复过程，不再需要无嘌呤核酸内切酶 1 (APE1)，而是依赖于多核苷酸激酶磷酸酶 (PNKP1) 活性。用小分子增加对氧化性 DNA 损伤的修复可能在各种疾病和衰老中具有治疗应用。
据了解，氧化性 DNA 损伤由OGG1识别，它切除 8-oxoG，留下APE1的底物并启动修复。
附：英文原文
Title: Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
Author: Maurice Michel, Carlos Benítez-Buelga, Patricia A. Calvo, Bishoy M. F. Hanna, Oliver Mortusewicz, Geoffrey Masuyer, Jonathan Davies, Olov Wallner, Kumar Sanjiv, Julian J. Albers, Sergio Castaeda-Zegarra, Ann-Sofie Jemth, Torkild Visnes, Ana Sastre-Perona, Akhilesh N. Danda, Evert J. Homan, Karthick Marimuthu, Zhao Zhenjun, Celestine N. Chi, Antonio Sarno, Elisée Wiita, Catharina von Nicolai, Anna J. Komor, Varshni Rajagopal, Sarah Müller, Emily C. Hank, Marek Varga, Emma R. Scaletti, Monica Pandey, Stella Karsten, Hanne Haslene-Hox, Simon Loevenich, Petra Marttila, Azita Rasti, Kirill Mamonov, Florian Ortis, Fritz Schmberg, Olga Loseva, Josephine Stewart, Nicholas D’Arcy-Evans, Tobias Koolmeister, Martin Henriksson, Dana Michel, Ana de Ory, Lucia Acero, Oriol Calvete, Martin Scobie, Christian Hertweck, Ivan Vilotijevic, Christina Kalderén, Ana Osorio, Rosario Perona, Alexandra Stolz, Pl Stenmark, Ulrika Warpman Berglund, Miguel de Vega, Thomas Helleday
Issue&Volume: 2022-06-24
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.
DOI: abf8980
Source: https://www.science.org/doi/10.1126/science.abf8980