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Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21 (RNA-Seq)

ABSTRACT: PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternate pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduce DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115760 | GEO | 2019/07/31

REPOSITORIES: GEO

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Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21

Project description:PARP inhibitors (PARPi) are thought to control cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternate pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADPribosylates DDX21, an RNA helicase that localizes to the rDNA locus and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites on DDX21 causes a reduction in rDNA transcription, as well as a reduction in ribosome biogenesis, protein translation, and cell growth. Our studies provide mechanistic insights into PARP-1-dependent ADP-ribosylation of DDX21 and its role in ribosome biogenesis. This pathway can be targeted for disruption in cancer cells that lack defects in DNA repair, but exhibit growth inhibition in response to PARPi.

2019-07-31 | GSE115761 | GEO

Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21 (RIP-Seq)

2019-07-31 | GSE115759 | GEO

ADP-ribosylation Levels Correlate with Gene Expression Patterns and Clinical Outcomes in Ovarian Cancers

Project description:Inhibitors of nuclear poly(ADP-ribose) polymerase (PARP) enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes.

2019-10-01 | GSE136155 | GEO

A genome-wide CRISPR screen identifies ZNF251 critical for resistance to PARP inhibitors

Project description:The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially these harboring BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting accumulation of toxic DSBs. Unfortunately, PARP inhibitor (PARPi) resistance is common and develops through multiple mechanisms. Restoration of HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we undertook an unbiased approach with a CRISPR-pooled library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and confirmed its loss-of-function led to the PARPi resistance in BRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi. Taken together, our study identified a novel gene whose loss of function conferred resistance to PARPi, providing new insight into signaling pathways that contribute to acquired resistance in BRCA1-mutated breast and ovarian cancers.

2023-05-31 | GSE205221 | GEO

Role of ALDH1A1 in PARPi resistance in ovarian cancer

Project description:Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Our previous study has demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells, mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, an ALDH1A1 selective inhibitor can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. In order to elucidating the mechanism by which ALDH1A1 renders PARPi resistance to ovarian cancer, we performed RNA-seq analysis to identify genes whose expression can be regulated by ALDH1A1.

2023-07-19 | GSE226018 | GEO

Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: ADP-Ribosylation

Project description:BRCA1/2-deficient ovarian carcinoma (OC) has been shown to be particularly sensitive to PARP inhibitors (PARPis) and BRCA1/2 mutation status is currently used as a predictive biomarker for PARPi therapy. Despite eliciting major clinical benefit for the majority of patients, a significant proportion of BRCA1/2-deficient OC tumors do not respond to PARPis for reasons that are incompletely understood. Using an integrated chemical, phospho- and ADP-ribosylation proteomics approach we sought to develop additional mechanism-based biomarker candidates for PARPi therapy in OC and identify new targets for combination therapy to overcome primary resistance. Chemical proteomics with PARPi baits in a BRCA1-isogenic OC cell line pair, as well as patient-derived BRCA1-profiecient and deficient tumor samples, and subsequent validation by co-immunoprecipitation showed differential PARP1 and PARP2 protein complex composition with Ku70 and Ku80 in PARPi-sensitive, BRCA1-deficient UWB1.289 (UWB) cells compared to PARPi-insensitive, BRCA1-reconstituted UWB1.289 (UWB+B) cells. Global phosphoproteomics and ADP-ribosylation proteomics furthermore revealed that rucaparib induced the cell cycle pathway and NHEJ pathway in UWB cells, but down-regulated ErbB signaling in UWB+B cells. In addition, we observed AKT PARylation and pro-survival AKT-mTOR signaling in UWB+B cells after PARPi treatment. Consistently, synergy of PARPis with DNAPK or AKT inhibitors was more pronounced in UWB+B cells identifying these pathways as actionable vulnerabilities. In conclusion, the combination of chemical proteomics, phosphoproteomics and ADP-ribosylation proteomics can identify differential PARP1/2 complexes and diverse, but actionable drug compensatory signaling in OC.

2022-10-21 | PXD029428 | Pride

Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: Phosphoproteomics

2022-10-21 | PXD029432 | Pride

Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: Chemical Proteomics

Project description:BRCA1/2-deficient ovarian carcinoma (OC) has been shown to be particularly sensitive to PARP inhibitors (PARPis) and BRCA1/2 mutation status is currently used as a predictive biomarker for PARPi therapy. Despite eliciting major clinical benefit for the majority of patients, a significant proportion of BRCA1/2-deficient OC tumors do not respond to PARPis for reasons that are incompletely understood. Using an integrated chemical, phospho- and ADP-ribosylation proteomics approach, we sought to develop additional mechanism-based biomarker candidates for PARPi therapy in OC and identify new targets for combination therapy to overcome primary resistance. Chemical proteomics with PARPi baits in a BRCA1-isogenic OC cell line pair, as well as patient-derived BRCA1-profiecient and deficient tumor samples, and subsequent validation by co-immunoprecipitation showed differential PARP1 and PARP2 protein complex composition with Ku70 and Ku80 in PARPi-sensitive, BRCA1-deficient UWB1.289 (UWB) cells compared to PARPi-insensitive, BRCA1-reconstituted UWB1.289 (UWB+B) cells. Global phosphoproteomics and ADP-ribosylation proteomics furthermore revealed that rucaparib induced the cell cycle pathway and NHEJ pathway in UWB cells, but down-regulated ErbB signaling in UWB+B cells. In addition, we observed AKT PARylation and pro-survival AKT-mTOR signaling in UWB+B cells after PARPi treatment. Consistently, synergy of PARPis with DNAPK or AKT inhibitors was more pronounced in UWB+B cells identifying these pathways as actionable vulnerabilities. In conclusion, the combination of chemical proteomics, phosphoproteomics and ADP-ribosylation proteomics can identify differential PARP1/2 complexes and diverse, but actionable drug compensatory signaling in OC.

2022-10-21 | PXD029424 | Pride

A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant

Project description:Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.

2023-07-18 | PXD040430 | Pride

Single cell RNA sequence reveals C5aR1 inhibition selectively targets pro-tumorigenic M2 macrophages reversing PARP inhibitor resistance

Project description:Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient thus requiring the development of combination therapies that can capitalize on PARPi activity. We thus explored mechanisms underlying sensitivity and resistance to PARPi using two intrinsically sensitive and resistant syngeneic murine breast cancer models. Our data indicate that the PARPi sensitive tumor model has a high ratio of M1 anti-tumor/M2 pro-tumor macrophages with the M1/M2 ratio being increased by PARPi. In contrast the PARPi resistant tumor model had very low levels of M1 macrophages and thus a low M1/M2 ratio that was not altered by PARPi. Our data indicate that co-transplantation of the PARPi sensitive and the PARPi resistant tumor results in accumulation of M2 macrophages in the sensitive tumor, rendering the sensitive tumor PARPi resistant. C5aR1 and RPS19/C5aR1 signaling is selectively elevated in the M2 macrophages that are associated with PARPi resistance. Strikingly C5aR1 targeting decreased M2 macrophages, while sparing M1 macrophages rendering PARPi resistant tumors sensitive to PARPi. Consistent with the murine data, human breast cancers with high C5aR1 levels have a poor response to immune checkpoint blockade. Thus targeting C5aR1 may represent a therapeutic approach to selectively deplete M2 macropahges and engender sensitivity to PARPi and potentially other therapeutic approaches.

2023-06-30 | GSE215908 | GEO

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