Ligand-Directed Caging Enables the Control of Endogenous DNA Alkyltransferase Activity with Light inside Live Cells
-
作者
Zhang, Yixin; Han, Lili; Tian, Xiaoxu; Peng, Chao; Chen, Yiyun
-
刊物名称
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
-
年、卷、文献号
2022, 61, 1433-7851
-
关键词
Zhang, Yixin; Han, Lili; Tian, Xiaoxu; Peng, Chao; Chen, Yiyun
-
摘要
The control of endogenous protein activity with light inside live cells is helpful for the high spatiotemporal probing of their dynamic roles. Herein, we report the first small-molecule-ligand-directed caging approach to control the endogenous human O-6-alkylguanine-DNA alkyltransferase (AGT) activity with light, and the caged AGT is constructed from the native intracellular AGT. The photo-responsive O-6-benzylguanine derivative O-6-NBG3 is developed to site-specifically cage the AGT's catalytic cysteine residue, and the light irradiation on-demand restores AGT's activity in vitro, in bacteria, and in mammalian cells. With O-6-NBG3, the alkylated AGT is dealkylated for the first time to recover the DNA repair activity in breast cancer MCF-7 cells by the dose-dependent light irradiation. This decaging strategy enables the localized modulation of endogenous AGT activity with high temporal precision without genetic engineering, which holds great potential for therapeutic applications.
