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

  1. Chiho Kim
  2. Xu-Dong Wang
  3. Yonghao Yu  Is a corresponding author
  1. University of Texas Southwestern, United States
  2. 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.

Article and author information

Author details

  1. Chiho Kim

    Department of Biochemistry, University of Texas Southwestern, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6846-5515
  2. Xu-Dong Wang

    Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8265-1485
  3. Yonghao Yu

    Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States
    For correspondence
    yonghao.yu@utsouthwestern.edu
    Competing interests
    Yonghao Yu, A patent application on the PARP degraders was previously filed (PCT/US2020/016129)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8414-4666

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.

Reviewing Editor

  1. Hening Lin, Cornell University, United States

Version history

  1. Received: July 1, 2020
  2. Accepted: August 25, 2020
  3. Accepted Manuscript published: August 26, 2020 (version 1)
  4. Version of Record published: September 11, 2020 (version 2)

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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  1. Chiho Kim
  2. Xu-Dong Wang
  3. Yonghao Yu
(2020)
PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response
eLife 9:e60637.
https://doi.org/10.7554/eLife.60637

Share this article

https://doi.org/10.7554/eLife.60637

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