PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response.

Chiho Kim,Xu-Dong Wang,Yonghao Yu

doi:10.7554/elife.60637

Abstract

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.

Highlights

Poly-ADP-ribose polymerase 1 is an enzyme that is critically involved in mediating DNA damage response (DDR)
It is being increasingly appreciated that chemo- and radiation-therapy cause the formation of cytosolic dsDNA and micronuclei, which, in turn, lead to the activation of the cGAS-Stimulator of Interferon Genes (STING) signaling pathway and inflammatory responses in tumors (Vanpouille-Box et al, 2018; Liang and Peng, 2016; Harding et al, 2017; Mackenzie et al, 2017; Dou et al, 2017; Gluck et al, 2017; Vanpouille-Box et al, 2017; Yum et al, 2019)
We explored the immunomodulatory functions of PARP1 inhibitors (PARPi) using Talazoparib, which is an FDA-approved PARP1 inhibitor that is known to potently inhibit and trap PARP1 (Figure 1A)

Summary

Introduction

Poly-ADP-ribose polymerase 1 (hereafter referred to as PARP1) is an enzyme that is critically involved in mediating DNA damage response (DDR). Besides the PARylationdependent mechanism, several recent studies suggest that the various clinically relevant PARPi all bind to PARP1, they induce different degrees of PARP1 conformational changes, and in doing so, PARP1 trapping (Lord and Ashworth, 2017; Hopkins et al, 2019; Murai et al, 2014; Shen et al, 2013; Murai et al, 2012). Because PARPi treatment is known to produce cytosolic dsDNA (double-stranded DNA), it has been proposed that the activation of innate immune signaling could be a critical molecular mechanism underlying the therapeutic effect of PARPi (Ding et al, 2018; Shen et al, 2019; Pantelidou et al, 2019; Sen et al, 2019). These results provide evidence that PARPi-mediated PARP1 trapping, but not the catalytic inhibition of PARP1, is a key determinant for the activation of the innate immune response

Results

Discussion

Materials and methods