Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting DKC1-mediated pseudouridylation combined with PARPi induces synthetic lethality in HR-proficient tumors [RNA-Seq]

ABSTRACT: Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment landscape of BRCA-mutant tumors by exploiting synthetic lethality arising from homologous recombination (HR) deficiency. Yet, a substantial proportion of solid tumors remain HR-proficient and thus less responsive to PARPi, underscoring the need to develop strategies that extend their therapeutic scope. Here, we uncover a previously unrecognized synthetic lethal interaction between PARPi and dyskerin (DKC1), an RNA pseudouridine synthase. By analyzing a publicly available genome-wide CRISPR-Cas9 screen conducted in the presence of niraparib, we identified DKC1 as a top candidate whose loss synergized with PARP inhibition to selectively kill HR-proficient cancer cells. Mechanistically, DKC1 depletion impaired pseudouridylation of chromatin-associated RNAs, particularly promoter-associated RNAs, resulting in reduced chromatin accessibility and compromised recruitment of DNA repair factors, including BRCA1 and RAD21. This chromatin remodeling phenocopies HR deficiency, rendering HR-proficient cells vulnerable to PARPi. Notably, co-targeting DKC1 and PARP elicited potent antitumor effects in vitro and in multiple HR-proficient xenograft models. These findings identify DKC1-mediated pseudouridylation as a critical determinant of chromatin structure and DNA repair fidelity, and extend the conceptual framework of synthetic lethality from genetic HR defects to epigenetic regulation, offering a promising strategy to broaden the clinical utility of PARPi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313124 | GEO | 2026/08/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other
	GSE313124_dge_RPKM.txt.gz	Txt

Items per page:

1 - 2 of 2

Similar Datasets

Targeting DKC1-mediated pseudouridylation combined with PARPi induces synthetic lethality in HR-proficient tumors [ATAC-seq]

Project description:Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment landscape of BRCA-mutant tumors by exploiting synthetic lethality arising from homologous recombination (HR) deficiency. Yet, a substantial proportion of solid tumors remain HR-proficient and thus less responsive to PARPi, underscoring the need to develop strategies that extend their therapeutic scope. Here, we uncover a previously unrecognized synthetic lethal interaction between PARPi and dyskerin (DKC1), an RNA pseudouridine synthase. By analyzing a publicly available genome-wide CRISPR-Cas9 screen conducted in the presence of niraparib, we identified DKC1 as a top candidate whose loss synergized with PARP inhibition to selectively kill HR-proficient cancer cells. Mechanistically, DKC1 depletion impaired pseudouridylation of chromatin-associated RNAs, particularly promoter-associated RNAs, resulting in reduced chromatin accessibility and compromised recruitment of DNA repair factors, including BRCA1 and RAD21. This chromatin remodeling phenocopies HR deficiency, rendering HR-proficient cells vulnerable to PARPi. Notably, co-targeting DKC1 and PARP elicited potent antitumor effects in vitro and in multiple HR-proficient xenograft models. These findings identify DKC1-mediated pseudouridylation as a critical determinant of chromatin structure and DNA repair fidelity, and extend the conceptual framework of synthetic lethality from genetic HR defects to epigenetic regulation, offering a promising strategy to broaden the clinical utility of PARPi.

2026-08-14 | GSE312874 | GEO

Targeting DKC1-mediated pseudouridylation combined with PARPi induces synthetic lethality in HR-proficient tumors

2026-08-14 | GSE312872 | GEO

PARP inhibition induces cytotoxicity in mESCs by activating endogenous retroviruses [ATAC-seq]

Project description:PARP inhibitors (PARPi) have been approved to treat patients with BRCA-deficient cancers via synthetic lethality. How PARPi kill BRCA-proficient cells remains an important unanswered question. Here we provide evidence that naïve murine embryonic stem cells, although being homologous-recombination potent, are very sensitive to PARPi such as Talazoparib (Tal). Tal acts on ARTD1 and activates p53 by blocking TOP2A dissociation from chromatin. Genome-wide CRISPR screening showed that the loss of TET1 reduces Tal induced cytotoxicity, which is recapitulated by the depletion of TDG. TET and TDG mediated DNA demethylation turnover renders the local chromatin accessible and facilitates p53 dependent transcription. Consequently, Tal treatment strongly activates the expression of endogenous retroviruses in a p53- and TET/TDG-dependent manner. The uncovered contribution of TET/TDG into Tal induced cytotoxicity sheds further light on future personalized medicine and suggests that TET/TDG mediated active DNA demethylation may represent a biomarker for the predication of sensitivity to PARPi.

2026-05-11 | GSE166962 | GEO

Targeting the ATM-TRMT10A-BRCA1 Axis Confers Synthetic Lethality to PARP Inhibition in Metastatic Castration-Resistant Prostate Cancer

Project description:Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease characterized by its aggressive nature and resistance to anti-androgen therapies. Although PARP inhibitors (PARPis) have brought new hope for mCRPC patients with homologous recombination (HR) deficient, such as those lacking BRCA1/2, the utility of PARPi monotherapy is significantly restricted, with only 10%-15% of mCRPC patients with BRCA1/2 deficiencies achieving clinical benefit. Thus, there is a critical need for innovative therapeutic strategies for mCRPC patients without BRCA deficiency. In our current study, we elucidate the pivotal role of the ATM-TRMT10A-BRCA1 axis in mediating HR repair and PARPi resistance in mCRPC. We demonstrate that TRMT10A is phosphorylated at S28 by ATM after DNA damage. This phosphorylation is essential for the recruitment of BRCA1 to sites of DNA damage, thereby facilitating HR repair. Deletion of TRMT10A compromises HR repair, rendering tumor cells more sensitive to PARPi. Importantly, we show that TRMT10A expression is upregulated in mCRPC and is modulated by Ubiquitin Specific Peptidase 10 (USP10). Inhibition of USP10 with small molecular inhibitor Spautin-1 leads to TRMT10A degradation and enhances the sensitivity of tumors to PARPi in both cell-derived xenografts (CDX) and patient-derived xenografts (PDX). Our findings underscore the vital role of ATM-TRMT10A-BRCA1 axis in the vulnerability to PARP inhibitors and introduce a promising strategy perspective for exploring synthetic lethality. This approach, which involves the combination of PARP and USP10 inhibitors, could extend therapeutic benefits to a broader group of mCRPC patients without BRCA mutation.

2024-12-30 | PXD059301 |

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

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

Project description: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.

2019-07-31 | GSE115760 | GEO

ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (ATAC-seq)

Project description:The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair mechanisms and the abundance of lesions that trap PARP enzymes on chromatin. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR based screen, we identify the PAR-binding Snf2-like ATPase, ALC1 as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA mutant cells and enhanced their sensitivity to PARPi by up to 250-fold, while overcoming several known resistance mechanisms. ALC1 loss was not epistatic to other repair pathways that execute the PARPi response. Instead, ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of repair factors. This resulted in an accumulation of replication associated DNA damage and a reliance on HR. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses, implicating ALC1 inhibition as a new approach to overcome therapeutic resistance in HR-deficient cancers.

2020-12-02 | GSE150955 | GEO

ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (RNA-seq)

2020-12-02 | GSE149104 | GEO

Effect of knockdown OFD1 on gene expression in pancreatic cancer cells

Project description:PARP inhibitors (PARPi) have demonstrated efficacy in treating human cancers with BRCA1 or BRCA2 gene mutations, which are present in only a small portion of breast, ovarian, prostate, and pancreatic cancers. In this study, we discovered that OFD1 is highly expressed in pancreatic cancer and is associated with a poor prognosis. Through screening an FDA-approved drug library, we found that OFD1 knockdown synergizes most effectively with PARPi for the treatment of pancreatic cancer cells. To explore the mechanism of OFD1 knockdown and PARP inhibitor-induced synthetic lethality, we knocked down OFD1 in three pancreatic cancer cell lines and performed RNA sequencing analysis of the whole genome to investigate the mechanisms underlying OFD1 inhibition and PARP inhibitor-induced synthetic lethality. In summary, our research will provide insights into the role of OFD1 in pancreatic cancer by revealing changes in the whole-genome expression profile and the underlying mechanisms.

2025-06-08 | GSE282746 | GEO

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data