Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), 28029 Madrid, Spain.
Science. 2022 Jun 24;376(6600):1471-1476. doi: 10.1126/science.abf8980. Epub 2022 Jun 23.
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.
氧化 DNA 损伤被 8-氧鸟嘌呤（8-oxoG）DNA 糖基化酶 1（OGG1）识别，OGG1 切除 8-oxoG，留下脱嘌呤内切酶 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-裂合酶酶功能。TH10785 通过其分子结构内的氮碱基控制催化活性。在细胞中，TH10785 增加了 OGG1 对氧化 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。小分子增加氧化 DNA 损伤的修复可能在各种疾病和衰老中具有治疗应用。
