DNA修复
化学
癌症研究
中性粒细胞胞外陷阱
PARP抑制剂
作者
Chiho Kim,X Wang,Yonghao Yu
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2020-08-26
卷期号:9
被引量:60
摘要
It is being increasingly appreciated that the immunomodulatory functions of PARP1 inhibitors (PARPi) underlie their clinical activities in various BRCA -mutated tumors. PARPi possess both PARP1 inhibition and PARP1 trapping activities. The relative contribution of these two mechanisms toward PARPi-induced innate immune signaling, however, is poorly understood. We find that the presence of the PARP1 protein with uncompromised DNA-binding activities is required for PARPi-induced innate immune response. The activation of cGAS-STING signaling induced by various PARPi closely depends on their PARP1 trapping activities. Finally, we show that a small molecule PARP1 degrader blocks the enzymatic activity of PARP1 without eliciting PARP1 trapping or cGAS-STING activation. Our findings thus identify PARP1 trapping as a major contributor of the immunomodulatory functions of PARPi. Although PARPi-induced innate immunity is highly desirable in human malignancies, the ability of ‘non-trapping’ PARP1 degraders to avoid the activation of innate immune response could be useful in non-oncological diseases.
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