当前位置: X-MOL 学术Science › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
Science ( IF 56.9 ) Pub Date : 2022-06-23 , DOI: 10.1126/science.abf8980
Maurice Michel 1 , Carlos Benítez-Buelga 1, 2 , Patricia A Calvo 3 , Bishoy M F Hanna 1 , Oliver Mortusewicz 1 , Geoffrey Masuyer 4, 5 , Jonathan Davies 5 , Olov Wallner 1 , Kumar Sanjiv 1 , Julian J Albers 1 , Sergio Castañeda-Zegarra 1, 6 , Ann-Sofie Jemth 1 , Torkild Visnes 7 , Ana Sastre-Perona 8 , Akhilesh N Danda 1 , Evert J Homan 1 , Karthick Marimuthu 1 , Zhao Zhenjun 1 , Celestine N Chi 9 , Antonio Sarno 10 , Elisée Wiita 1 , Catharina von Nicolai 1 , Anna J Komor 11 , Varshni Rajagopal 1 , Sarah Müller 1 , Emily C Hank 1 , Marek Varga 1 , Emma R Scaletti 5, 12 , Monica Pandey 1, 13 , Stella Karsten 1 , Hanne Haslene-Hox 7 , Simon Loevenich 7 , Petra Marttila 1 , Azita Rasti 1 , Kirill Mamonov 1 , Florian Ortis 1 , Fritz Schömberg 14 , Olga Loseva 1 , Josephine Stewart 1 , Nicholas D'Arcy-Evans 1 , Tobias Koolmeister 1 , Martin Henriksson 1 , Dana Michel 15 , Ana de Ory 16 , Lucia Acero 8 , Oriol Calvete 17 , Martin Scobie 1 , Christian Hertweck 11, 18 , Ivan Vilotijevic 14 , Christina Kalderén 1 , Ana Osorio 17, 19 , Rosario Perona 2, 19 , Alexandra Stolz 20 , Pål Stenmark 5, 12 , Ulrika Warpman Berglund 1 , Miguel de Vega 3 , Thomas Helleday 1, 13
Affiliation  

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.

中文翻译:

OGG1的小分子激活通过获得新功能来增加氧化性DNA损伤修复

氧化性 DNA 损伤由 8-氧鸟嘌呤 (8-oxoG) DNA 糖基化酶 1 (OGG1) 识别,它切除 8-oxoG,留下无嘌呤核酸内切酶 1 (APE1) 的底物并启动修复。在这里,我们描述了一种小分子 (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 APE1,而是依赖于多核苷酸激酶磷酸酶 (PNKP1) 活性。
更新日期:2022-06-23
down
wechat
bug