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. Department of Biochemistry, University of Texas Southwestern Medical Center, United States
4 figures, 1 table and 4 additional files

Figures

Figure 1 with 2 supplements
PARPi induces the innate immune response via the cGAS-STING pathway.

(A) The level of trapped PARP1 in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Top, chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the level of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with unpaired Student’s t-test. ***p < 0.001. (B) Staining of cytosolic dsDNA in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Left, representative image of PicoGreen (green) staining. DAPI (blue) was used to visualize the nucleus. Scale bars represent 10 μm. Right, the graph shows the quantification of the number of cells with cytosolic dsDNA. Values were presented as means ± SEM from three biological replicates (n = 3 fields,≥100 cells counted per condition). Significance was determined with unpaired Student’s t-test. ****p < 0.0001. (C) The extent of DNA damage in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of γH2AX levels. Values were presented as means ± SD from three biological replicates. Significance was determined with unpaired Student’s t-test. **p < 0.01. (D) The level of pS172 TBK1 in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of pS172 TBK1 levels. Values were presented as means ± SD from three biological replicates. Significance was determined with unpaired Student’s t-test. **p < 0.01. (E) The level of pS396 IRF3 in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Left, representative image of pS396 IRF3 levels (green). DAPI (blue) was used to visualize the nucleus. Scale bars represent 20 μm. Right, the graph shows the quantification of the number of cells stained positive for pS396 IRF3 in nucleus. Values were presented as means ± SEM from three biological replicates (n = 3 fields,≥100 cells counted per condition). Significance was determined with unpaired Student’s t-test. ***p < 0.001. (F) RT-qPCR of type I interferons levels in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Values of Inf-α and Inf-β were presented as means ± SEM from three biological replicates. Significance was determined with unpaired Student’s t-test. *p < 0.05, **p < 0.01. (G) Knock-down of cGAS. HeLa cells expressing the control shRNA (shScramble) or shcGAS (shcGAS #1 or #2) were probed using the indicated antibodies. Right, the graph shows the ratio of cGAS depletion. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. ***p < 0.001. (H) Depletion of cGAS abolishes PARPi-induced activation of innate immune signaling. HeLa cells expressing shRNA against control (shScramble) or cGAS (shcGAS #1 or #2) were treated with or without Talazoparib (10 µM for 72 hr). The cells were lysed and were immunoblotted using the indicated antibodies. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. ****p < 0.0001, n.s., not significant. (I) RT-qPCR analyses of type I interferons. HeLa cells expressing shRNA against control (shScramble) or cGAS (shcGAS #1 or #2) were treated with or without Talazoparib (10 µM for 72 hr). Values of Inf-α and Inf-β mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with unpaired Student’s t-test. ****p < 0.0001, n.s., not significant.

Figure 1—figure supplement 1
Proteomic profiling of PARPi-induced innate immune response (Part 1).

(A) RT-qPCR analyses of cGAS-STING target gene expression in HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Values of cytokines and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with unpaired Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. (B) The levels of trapped PARP1 in HeLa cells expressing shRNA against control (shScramble) or cGAS (shcGAS #1 or #2) that were treated with or without Talazoparib (10 µM for 72 hr). Top, chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the levels of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. ***p < 0.001, n.s., not significant. (C) The extent of DNA damage in HeLa cells expressing shRNA against control (shScramble) or cGAS (shcGAS #1 or #2) that were treated with or without Talazoparib (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of γH2AX levels. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. ***p < 0.001, n.s., not significant. (D) RT-qPCR analyses of cGAS-STING target gene expression in HeLa cells expressing shRNA against control (shScramble) or cGAS (shcGAS #1 or #2) that were treated with or without Talazoparib (10 µM for 72 hr). Values of cytokines and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with two-way ANOVA. ***p < 0.001, ****p < 0.0001, n.s., not significant.

Figure 1—figure supplement 2
Proteomic profiling of PARPi-induced innate immune response (Part 2).

(E) The levels of trapped PARP1 in MHH-ES-1 cells treated with or without Talazoparib (1 µM for 24 hr). Top, chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the level of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with unpaired Student’s t-test. **p < 0.01. (F) The extent of DNA damage in MHH-ES-1 cells treated with or without Talazoparib (1 µM for 24 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of γH2AX levels. Values were presented as means ± SD from three biological replicates. Significance was determined with unpaired Student’s t-test. **p < 0.01. (G) The level of pS172 TBK1 in MHH-ES-1 cells treated with or without Talazoparib (1 µM for 24 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of pS172 TBK1 levels. Values were presented as means ± SD from three biological replicates. Significance was determined with unpaired Student’s t-test. **p < 0.01. (H) Reproducibility of the TMT experiments. The signal-to-noise (SN) values of the corresponding TMT channels for each protein was extracted from the two biological replicate experiments. (I) Quantification of protein expression in MHH-ES-1 cells treated with Talazoparib 1 µM for 24 hr (Supplementary file 1). Top, the graph shows the log2 value of total protein expression in Talazoparib-treated vs. DMSO control. Bottom, the heatmap shows quantification reproducibility of the up- and down-regulated protein. Red: up-regulated proteins; Green: down-regulated proteins. (J) GO analysis of the up-regulated proteins as shown in (I). The list shows the top 10 enriched biological processes of the up-regulated proteins. (K) RT-qPCR analyses of the cGAS-STING target gene expression in MHH-ES-1 cells treated with or without Talazoparib (1 µM for 24 hr). Values of type I interferons, cytokines, and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with unpaired Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Figure 2 with 1 supplement
The PARP1 protein is required for PARPi-induced innate immune signaling.

(A) PARPi-induced PARP1 trapping in wild-type (WT) and PARP1 knockout (KO) HeLa cells. Cell were also treated with or without Talazoparib (10 µM for 72 hr). Top, chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the level of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. ****p < 0.001, n.s., not significant. (B) DDR in WT and PARP1 KO HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of γH2AX levels. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. ***p < 0.001, n.s., not significant. (C) The level of pS172 TBK1 in WT and PARP1 KO HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of pS172 TBK1 levels. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. ****p < 0.0001, n.s., not significant. (D) Staining of pS396 IRF3 levels in WT and PARP1 KO HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Left, a representative image of pS396 IRF3 levels (green). DAPI (blue) was used to visualize the nucleus. Right, the graph shows the quantification of the number of cells stained positive for pS396 IRF3 in the nucleus. Values were presented as means ± SEM from three biological replicates. Significance was determined with two-way ANOVA. ****p < 0.0001, n.s., not significant. (E) RT-qPCR analyses of type I interferons in WT and PARP1 KO HeLa cells treated with or without Talazoparib (10 µM for 72 hr). Values of Inf-α and Inf-β mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with two-way ANOVA. *p < 0.05, **p < 0.01, n.s., not significant.

Figure 2—figure supplement 1
The PARP1 protein is required for PARPi-induced innate immune response.

(A) The level of PARP1 in WT and PARP1 KO HeLa cells. Whole cell lysates were probed using the indicated antibodies. GAPDH used as the loading control. (B) RT-qPCR analyses of cGAS-STING target gene expression in WT and PARP1 KO HeLa cells that were treated with or without Talazoparib (10 µM for 72 hr). Values of cytokines and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with two-way ANOVA. **p < 0.01, ***p < 0.001, ****p < 0.001, n.s., not significant.

Figure 3 with 1 supplement
PARP1 trapping is the major contributor of PARPi-induced innate immune signaling.

(A) The level of trapped PARP1 in HeLa cells treated with or without the indicated PARPi (10 µM for 72 hr). Top, chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the level of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. *p < 0.05, ***p < 0.001. (B) The extent of DNA damage in HeLa cells treated with or without the indicated PARPi (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of γH2AX levels. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. **p < 0.01, ***p < 0.001. (C) The level of pS172 TBK1 in HeLa cells treated with or without the indicated PARPi (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of pS172 TBK1 levels. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. *p < 0.05, ***p < 0.001. (D) Heatmap of PARP1 trapping, DNA damage, and pS172 TBK1 levels for each PARPi. The normalized levels of PARP1 trapping (A), γH2AX (B), and pS172 TBK1 (C) are shown. (E) PARPi does not induce the trapping of a PARP1 mutant with defective DNA binding. Top, HeLa PARP1 KO cells expressing WT PARP1 or R138C mutant PARP1 (R138C) were treated with or without Talazoparib (10 µM for 72 hr). Chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the levels of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. **p < 0.01, ***p < 0.001. (F) The extent of DNA damage in HeLa PARP1 KO cells expressing WT PARP1 or R138C PARP1 that were treated with or without Talazoparib (10 µM for 72 hr). Left, whole cell lysates were probed using the indicated antibodies. Right, the graph shows the quantification of γH2AX and pS172 TBK1 levels. Values were presented as means ± SD from three biological replicates. Significance was determined with two-way ANOVA. **p < 0.01, ***p < 0.001. (G) RT-qPCR analyses of type I interferons in HeLa PARP1 KO cells expressing WT or R138C PARP1 that were treated with or without Talazoparib (10 µM for 72 hr). Values of Inf-α and Inf-β mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with two-way ANOVA. **p < 0.01, ***p < 0.001.

Figure 3—figure supplement 1
PARP1 trapping is required for PARPi-induced cytotoxicity and innate immune response.

(A) The levels of PAR signals in HeLa cells treated with the indicated PARPi (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of PAR levels. GAPDH was used as the loading control. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. ***p < 0.001. (B) RT-qPCR analyses of cGAS-STING target gene expression in HeLa cells treated with Talazoparib or Rucaparib (10 µM for 72 hr). Values of type I interferons, cytokines, and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with one-way ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. (C) RT-qPCR analyses of cGAS-STING target gene expression in HeLa PARP1 KO cells expressing PARP1 WT or R138C that were treated with or without Talazoparib (10 µM for 72 hr). Values of cytokines and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with one-way ANOVA. **p < 0.01, ***p < 0.001. (D) Cell death analyses. MHH-ES-1 cells were treated with the PARP inhibitors as indicated (1 µM for 24 hr). Cell viability was measured by CellTiter-Glo assays. Cell survival is presented as means ± SEM from three biological replicates. Significance was determined with one-way ANOVA. ***p < 0.001, ****p < 0.0001.

Figure 4 with 1 supplement
PARP1 degraders abolish PARP1-trapping induced innate immune signaling.

(A) The level of PARP1 in HeLa cells treated with either Rucaparib or iRucaparib-AP6 (10 µM for 72 hr). Whole cell lysates were probed using the indicated antibodies. GAPDH was used as the loading control. (B) The level of trapped PARP1 in HeLa cells treated with either Rucaparib or iRucaparib-AP6 (10 µM for 72 hr). Top, chromatin-bound fractions were isolated and were probed using the indicated antibodies. Histone H3 was used as the loading control. Bottom, the graph shows the quantification of the level of PARP1 trapping. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. ***p < 0.001. (C) The extent of DNA damage in HeLa cells treated with either Rucaparib or iRucaparib-AP6 (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of γH2AX levels. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. ***p < 0.001. (D) The level of pS172 TBK1 in HeLa cells treated with either Rucaparib or iRucaparib-AP6 (10 µM for 72 hr). Top, whole cell lysates were probed using the indicated antibodies. Bottom, the graph shows the quantification of pS172 TBK1 levels. Values were presented as means ± SD from three biological replicates. Significance was determined with one-way ANOVA. **p < 0.01. (E) RT-qPCR analyses of the cGAS-STING target gene expression in HeLa cells treated with either Rucaparib or iRucaparib-AP6 (10 µM for 72 hr). Values of type I interferons, cytokines, and ISGs mRNA levels were presented as means ± SEM from three biological replicates. Significance was determined with one-way ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. (F) The model of the activation of innate immune response via PARPi-induced PARP1 trapping.

Figure 4—figure supplement 1
PARP1 degraders prevent PARP1 trapping-induced cytotoxicity.

(A) Cell death analyses. MHH-ES-1 cells were treated with Rucaparib or iRucaparib-AP6 as indicated (1 µM for 24 hr). Cell viability was measured by CellTiter-Glo assays. Cell survival is presented as means ± SEM from three biological replicates. Significance was determined with one-way ANOVA. ***p < 0.001, ****p < 0.0001.

Tables

Key resources table
Reagent type
(species) or resource
DesignationSource or referenceIdentifiersAdditional
information
AntibodyAnti-PAR (Mouse monoclonal)TrevigenCat# 4335-MC-100,
RRID:AB_2572318
IB (1:3000)
AntibodyAnti-PARP1 (Rabbit polyclonal)Cell Signaling TechnologyCat# 9542,
RRID:AB_2160739
IB (1:1000)
AntibodyAnti-γH2AX (Rabbit monoclonal)Cell Signaling TechnologyCat# 9718,
RRID:AB_2118009
IB (1:3000)
AntibodyAnti-Histone H3 (Rabbit monoclonal)Cell Signaling TechnologyCat# 4499,
RRID:AB_10544537
IB (1:3000)
AntibodyAnti-GAPDH
(Mouse monoclonal)
Santa Cruz BiotechnologyCat# sc-32233,
RRID:AB_627679
IB (1:5000)
AntibodyAnti-Phospho-TBK1/NAK (pS172 TBK1) (Rabbit monoclonal)Cell Signaling TechnologyCat# 5483,
RRID:AB_10693472
IB (1:1000)
AntibodyAnti-TBK1/NAK (Rabbit monoclonal)Cell Signaling TechnologyCat# 3504,
RRID:AB_2255663
IB (1:1000)
AntibodyAnti-Flag (Rabbit polyclonal)MilliporeSigmaCat# F7425,
RRID:AB_439687
IB (1:1000)
AntibodyAnti-cGAS (Rabbit monoclonal)Cell Signaling TechnologyCat# 15102,
RRID:AB_2732795
IB (1:1000)
AntibodyAnti-Phospho-IRF-3 (pS396 IRF3) (Rabbit monoclonal)Cell Signaling TechnologyCat# 4947,
RRID:AB_823547
IF (1:1000)
AntibodyAlexa Fluor 488-conjugated goat anti-rabbit IgG (Goat polyclonal)Thermo Fisher ScientificCat# A32731,
RRID:AB_2633280
IF (1:1000)
AntibodyGoat Anti-Mouse IgG Antibody, HRP conjugate, Species Adsorbed (Goat polyclonal)MilliporeSigmaCat# AP181P,
RRID:AB_11214094
IB (1:3000)
AntibodyECL Rabbit IgG, HRP-linked fragment (Donkey polyclonal)GE Healthcare life sciencesCat# NA9340,
RRID:AB_772191
IB (1:3000)
Chemical compound, drugTalazoparibSelleckCat# S7048PARP1 inhibitor
Chemical compound, drugNiraparibSelleckCat# S2741PARP1 inhibitor
Chemical compound, drugRucaparibSelleckCat# S1098PARP1 inhibitor
Chemical compound, drugOlaparibSelleckCat# S1060PARP1 inhibitor
Chemical compound, drugVeliparibSelleckCat# S1004PARP1 inhibitor
Chemical compound, drugiRucaparib-AP6Our laboratoryN/APARP1 degrader
Chemical compound, drugPolybrene (Hexadimethrine bromide)MilliporeSigmaCat# H9268; CAS 28728-55-4
Chemical compound, drugPuromycinMilliporeSigmaCat# P7255; CAS 58-58-2
Cell line (human)HeLaATCCCat# CCL-2,
RRID:CVCL_0030
Cell line (human)HeLa PARP1 KOIn this studyN/APARP1 deficient HeLa
Cell line (human)MHH-ES-1DSMZCat# ACC 167,
RRID:CVCL_1411
Cell line (human)HeLaATCCCat# CCL-2
Recombinant DNA reagentpCMV-hPARP1-3xFlag-WTAddgeneCat# 11157In pCMV; tagged with 3XFlag on its N-terminus
Recombinant DNA reagentpCMV-hPARP1-3xFlag-R138CIn this studyModified by R138C mutationIn pCMV; tagged with 3XFlag on its N-terminus
Strain, strain background (Escherichia coli)DH5alphaThermo Fisher ScientificCat# 18258012Competent cells
Strain, strain background (Escherichia coli)Stbl3 Competent E. coliThermo Fisher ScientificCat# C737303Competent cells
Commercial assay or kitQuant-iT PicoGreen dsDNA ReagentThermo Fisher ScientificCat# P7581
Commercial assay or kitSubcellular Protein Fractionation Kit for Cultured CellsThermo Fisher ScientificCat# 78840
Commercial assay or kitRNeasy Mini KitQIAGENCat# 74104
Commercial assay or kitQIAprep Spin Miniprep KitQIAGENCat# 27106
Commercial assay or kite-Myco PLUS Mycoplasma PCR Detection KitBOCA SCIENTIFICCat# 25237
Commercial assay or kitTMT6plex Mass Tag Labeling KitsThermo Fisher ScientificCat# 90110
Commercial assay or kitCellTiter-Glo Luminescent Cell Viability AssayPromegaCat# G7571
Software, algorithmImageJ 1.49 vNIHhttps://imagej.net/ImageJ2
Software, algorithmDAVID Bioinformatics Resources v6.8DAVIDhttps://david.ncifcrf.gov/
Software, algorithmPRISM v8.2.0GraphPadhttps://www.graphpad.com/scientific-software/prism/
Software, algorithmhuman protein sequences (Uniprot)UniProthttps://www.uniprot.org/UniProt database (2019_07,560,537 sequences;taxonomy, Homo sapiens, 20,431 )
Software, algorithmhuman IPI protein database v3.60EMBL-EBIftp://ftp.ebi.ac.uk/pub/databases/IPI
Software, algorithmThe Sequest algorithm v28Cell. 2010 Dec 3;143(7):1174–89N/A
OthersDAPIMilliporeSigmaCat# D9542
OthersDimethyl sulfoxide (DMSO)Thermo Fisher ScientificCat# BP231-1; CAS 67-68-5
OthersLipofectamine 2000Thermo Fisher ScientificCat# 11668500
OthersDulbecco’s Modified Eagle’s Medium (DMEM)MilliporeSigmaCat# D5796
OthersRPMI1640MilliporeSigmaCat# R8758
OthersFetal Bovine Serum (FBS)MilliporeSigmaCat# 12303C
OthersLysyl Endopeptidase (Lys-C)WakoCat# 129–02541; CAS 123175-82-6
OthersGen5BioTekN/A
OthersBCA reagentsThermo Fisher ScientificCat# 23224/23228
Others0.45 μm filterThermo Fisher ScientificCat# 05-713-387
OthersSynergy HT Multi-Detection Microplate Reader.BioTekN/A
OthersSuperScript III Reverse TranscriptaseThermo Fisher ScientificCat# 18080044
OthersCFX384 Touch Real-Time PCR Detection SystemBio-RadCat# 1855484
OthersApplied Biosystems Power SYBR Green PCR Master MixThermo Fisher ScientificCat# 43-676-59
OthersOasis HLB solid-phase extraction (SPE) cartridgesWatersCat# 186000383
Others3M Empore C18 Extraction DiskThermo Fisher ScientificCat# 14-386-2
OthersZORBAX 300Extend-C18 HPLC columnAgilentCat# 761775–902
OthersQ Exactive Hybrid Quadrupole-Orbitrap Mass SpectrometerThermo Fisher ScientificCat# IQLAAEGAAPFALGMAZR
OthersPicoFrit nanospray columnsNew ObjectivePF360-75-15-N-5

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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