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A chromatin re-localization screen for the identification of Poly-ADP-ribosylation (PARylation)-dependent DNA repair factors.

ABSTRACT: A chromatin re-localization screen for the identification of Poly-ADP-ribosylation (PARylation)-dependent DNA repair factors.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Chiho Kim

LAB HEAD: Yonghao Yu

PROVIDER: PXD045229 | Pride | 2024-01-26

REPOSITORIES: Pride

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Publications

Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in <i>BRCA</i>-mutated cancer.

Li Peng P Zhen Yuanli Y Kim Chiho C Liu Zhengshuai Z Hao Jianwei J Deng Heping H Deng Hejun H Zhou Min M Wang Xu-Dong XD Qin Tian T Yu Yonghao Y

Science advances 20231025 43

Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natura ...[more]

PMID: 37878693

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Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer (batch2-6)

Project description:A subset of small cell lung cancer (SCLC) shows a clinical response to PARP inhibitors (PARPi) despite being proficient in homologous repair pathways. However, the underlying mechanism(s) of PARPi sensitivity is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC is explained by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without homologous recombination deficiency.

2024-01-26 | PXD029968 | Pride

Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer

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Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

Project description:PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib (1) results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent “non-trapping” PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

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Measurements of mRNA abundance and decay for two strains 211 (wt) and 212 (mutant)

Project description:For each strain two time courses for mRNA abundance: Oxidative and MMS and two time courses for decay: reference decay and following oxidative stress We used Affymetrix microarrays to quantify changes in mRNA abundance following oxidative stress and DNA damage stress and also decay following transcription inhibition with and without oxidative stress. Each of the experiments were done for both strains 211 (wt) and 212 (mutant)

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2008-10-26 | E-GEOD-12220 | biostudies-arrayexpress

The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Expression Proteomics

Project description:PARP1 inhibitors (PARP1is ) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determined the differential efficacy of multiple clinical PARP1is in SCLC cells. Compared to the other PARP1is (rucaparib, olaparib and niraparib), talazoparib displayed the highest potency across SCLC, also in SLFN11-negative cells. Chemical proteomics identified PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduced cell survival, particularly in combination with PARP1 inhibition. Drug combination screening revealed talazoparib synergy with the WEE1/PLK1 inhibitor, adavosertib. Global phosphoproteomics identified disparate effects on cell cycle and DNA damage response signaling, illustrating underlying mechanisms. Synergy with adavosertib was more pronounced for talazoparib than olaparib and silencing PARP16 further reduced cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib’s overall mechanism of action and constitutes a new actionable target in SCLC.

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2019-08-01 | PXD014838 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014836 | Pride