PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response
- University of Texas Southwestern, United States
- UT Southwestern Medical Center, United States
Abstract
It is being increasingly appreciated that the immunomodulatory functions of PARP 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.
Data availability
The raw and analyzed TMT-MS data in MHH-ES-1 cells following Talazoparib treatment is provided in Supplementary file 1. Its GO analysis data using up-regulated proteins is provided in Supplementary file 2.
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Funding
National Institute of General Medical Sciences (R01GM122932)
- Yonghao Yu
National Institute of General Medical Sciences (R35GM134883)
- Yonghao Yu
Welch Foundation (I-1800)
- Yonghao Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response
eLife 9:e60637.
https://doi.org/10.7554/eLife.60637
