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.
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.
- Yonghao Yu
- Yonghao Yu
- Yonghao Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Hening Lin, Cornell University, United States
© 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.
Centrosomes act as the main microtubule organizing center (MTOC) in metazoans. Centrosome number is tightly regulated by limiting centriole duplication to a single round per cell cycle. This control is achieved by multiple mechanisms, including the regulation of the protein kinase PLK4, the most upstream facilitator of centriole duplication. Altered centrosome numbers in mouse and human cells cause p53-dependent growth arrest through poorly defined mechanisms. Recent work has shown that the E3 ligase TRIM37 is required for cell cycle arrest in acentrosomal cells. To gain additional insights into this process, we undertook a series of genome-wide CRISPR/Cas9 screens to identify factors important for growth arrest triggered by treatment with centrinone B, a selective PLK4 inhibitor. We found that TRIM37 is a key mediator of growth arrest after partial or full PLK4 inhibition. Interestingly, PLK4 cellular mobility decreased in a dose-dependent manner after centrinone B treatment. In contrast to recent work, we found that growth arrest after PLK4 inhibition correlated better with PLK4 activity than with mitotic length or centrosome number. These data provide insights into the global response to changes in centrosome number and PLK4 activity and extend the role for TRIM37 in regulating the abundance, localization, and function of centrosome proteins.
Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display upregulated cystathionine-β-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (H2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. CBS depletion allows AIS cells to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.