Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Repression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic Trioxide

ABSTRACT: The synergistic combination of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) has transformed acute promyelocytic leukemia (APL) from a terminal disease into a curable one. However, the molecular basis for the APL-specific synergy remains to be fully defined. In this work, we studied the mechanism that drives the unique efficacy of ATRA/ATO on APL cells. We found that the ATRA/ATO combination generates a high level of endogenous genotoxic stress, leading to exacerbated accumulation of DNA damage in APL cellular models and patient samples. Crucially, we found that ATRA-treatment triggers the ubiquitin-proteasome -mediated degradation of key DNA damage response proteins, including ATM and FANCD2. This APL-specific event is independent of PML-RARA turnover and creates a profound vulnerability to genotoxic stress, rendering APL cells more susceptible to the combined genotoxic stress from the ATRA-ATO combination. Our findings reveal that the synergized induction of genotoxic stress and the concurrent impairment of the DNA damage response mechanisms constitute a lethal "Double-Hit" that promotes APL-specific apoptosis. This study provides a novel paradigm for understanding therapeutic synergy and suggests that targeting DDR protein stability may extend the success of differentiation therapy to a broader range of leukemia.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lei Li

PROVIDER: PXD078309 | iProX | Wed May 13 00:00:00 GMT+01:00 2026

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Similar Datasets

Repression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic Trioxide

Project description:The synergistic combination of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) has transformed acute promyelocytic leukemia (APL) from a terminal disease into a curable one. However, the molecular basis for the APL-specific synergy remains to be fully defined. In this work, we studied the mechanism that drives the unique efficacy of ATRA/ATO on APL cells. We found that the ATRA/ATO combination generates a high level of endogenous genotoxic stress, leading to exacerbated accumulation of DNA damage in APL cellular models and patient samples. Crucially, we found that ATRA-treatment triggers the ubiquitin-proteasome -mediated degradation of key DNA damage response proteins, including ATM and FANCD2. This APL-specific event is independent of PML-RARA turnover and creates a profound vulnerability to genotoxic stress, rendering APL cells more susceptible to the combined genotoxic stress from the ATRA-ATO combination. Our findings reveal that the synergized induction of genotoxic stress and the concurrent impairment of the DNA damage response mechanisms constitute a lethal "Double-Hit" that promotes APL-specific apoptosis. This study provides a novel paradigm for understanding therapeutic synergy and suggests that targeting DDR protein stability may extend the success of differentiation therapy to a broader range of leukemia.

2026-05-16 | GSE330966 | GEO

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

Project description:The DNA-damaging agent gemcitabine (GEM) is a first-line treatment for pancreatic cancer but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs including kinase inhibitors but the experimental evidence for such rational is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 140 clinical kinase inhibitors and observed strong synergy for the ATR inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway including phosphorylated pS468 of CHEK1 as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

2024-03-18 | MSV000094340 | MassIVE

Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients

Project description:Frataxin, a conserved mitochondrial protein involved in iron homeostasis, is reduced in patients with Friedreich’s ataxia (FRDA). Transcription profiling and DNA damage assays were performed on blood cells from FRDA patients. Altered expression patterns pertained to immune response, signaling pathways, transcription, apoptosis, and genotoxic stress response pathways. FRDA patients had significantly more mitochondrial and nuclear DNA damage than a control population. Frataxin mRNA levels correlated with age of onset and displayed unique sets of gene alterations involved in oxidative phosphorylation and protein synthesis. Thus analysis of blood in FRDA patients yields insight into the nature and progression of the disease, as well as potential therapeutic approaches. Keywords: Friedreich's ataxia; frataxin; mitochondrial DNA damage; nuclear DNA damage; genotoxic stress

2009-12-08 | GSE11204 | GEO

An epigenomic role of Fe65 in the cellular response to DNA damage.

Project description:In this study, we hypothesized that the transcriptional activity of Fe65 may contribute to DNA damage pathways by regulating gene expression patterns activated in response to genotoxic stress. To address this hypothesis, we mapped the global binding profile of Fe65 by chromatin immunoprecipitation (ChIP)-sequencing in the SK-N-SH cells exposed to genotoxic stress. Unexpectedly, the genome-wide location analysis showed a substantial enrichment of Fe65 in the promoter regions of coding genes linked to DNA damage signaling pathways.

2017-03-29 | GSE97149 | GEO

RBM7 activates P-TEFb for a pro-survival transcriptional response to DNA damage

Project description:DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain obscure. Here we show that following DNA damage, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) elongation and increases cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by DNA damage-enhanced binding of RBM7 to 7SK, the scaffold of the 7SK small nuclear ribonucleoprotein (snRNP) that inhibits P-TEFb. As a result, P-TEFb relocates from 7SK snRNP to chromatin to activate transcription of key DDR genes and multiple classes of non-coding RNAs. By alleviating the inhibition of P-TEFb, RBM7 thus promotes Pol II elongation to activate a transcriptional response that is crucial for cell fate upon genotoxic insult. Our work highlights a novel paradigm in stress-dependent control of Pol II pause release, and offers the promise of combating cancer by RBM7 and P-TEFb antagonists in combination with established DNA damage-inducing chemotherapeutics.

2018-06-01 | E-MTAB-6475 | biostudies-arrayexpress

Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation

Project description:Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53-dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53-dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53-null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T-cell leukemia and lymphoma. Together, these data highlights coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance, and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation.

2015-05-20 | GSE69032 | GEO

SP6 safeguards human multipotent trophoblasts from DNA damage-induced ageing by shaping DNA-PK complex

Project description:The placenta can be threatened by DNA damage caused by genotoxic events. However, how placental trophoblasts coordinate cell type-restricted mechanisms in response to DNA damage and how they maintain genome stability remains elusive. We previously reported that the transcription factor SP6 regulates the fate of human cytotrophoblasts (CTs) and trophoblast stem cells (TSCs). Here, we demonstrate that SP6 interacts with DNA-PKcs in CTs and TSCs to shape the phosphorylation pattern of this kinase for DNA damage repair (DDR), a role that is independent of its transcriptional activity. Lack of SP6 leads to the inactivation of DNA-PKcs, defects in DNA-PK complex assembly and DDR, and eventually cell senescence. Moreover, pharmaceutically or genetically targeting OTUB1-SP6 regulatory axis, which controls the dynamic turnover of cellular SP6 during DDR, can reset the susceptibility of CTs or TSCs to genotoxic stress-induced DNA damage. Taken together, these findings identify a CT- or TSC-specific DDR mechanism, and we propose a potential druggable target for mitigating DNA damage and cell senescence-related human placental diseases.

2026-06-10 | GSE282143 | GEO

Synergistic Potential of CDK4/6 Inhibitors and ATRA in non-APL AML.

Project description:Background: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by diverse genetic abnormalities. The standard of care remains to be chemotherapy and stem cell transplantation. In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) has significantly improved outcomes. Despite this, the success of ATRA has yet to be transferred to non-APL AML. Exploring combinations to enhance the efficacy of ATRA in non-APL AML remains a key focus. Objective: To investigate the therapeutic effect of ATRA in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in non-APL AML. Methods: Non-APL AML cells and primary patient samples were treated with ATRA and CDK4/6 inhibitors. Key outcomes included differentiation, proliferation, cell viability, and colony-forming capacity. Combination synergy was evaluated, and gene expression analysis identified pathways associated with therapeutic effects. Results: The combination demonstrated dose-dependent effects, enhancing differentiation and reducing proliferation, cell viability, and colony-forming capacity. A synergistic effect was observed across AML cell lines. Gene expression profiling revealed the co-regulation of differentiation-associated genes, unveiling the mechanisms driving therapeutic synergy. Conclusion: Combination of CDK4/6 inhibitors with ATRA shows potential for differentiation-based AML treatment. This approach offers a promising avenue for improved outcomes in non-APL AML.

2025-03-18 | GSE291868 | GEO

PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

Project description:Trabectedin is a DNA-damaging agent with a peculiar mechanism of action; it traps the DNA repair machinery leading to DNA single- and double-strand breaks, particularly in BRCA1/2-deficient tumors. We hypothesized that trabectedin-induced DNA damage might activate PARP1 (a DNA-repair machinery key player), and consequently, PARP1 inhibition would perpetuate trabectedin-induced DNA damage. In several tumor histotypes, we demonstrated a different degree of synergism between trabectedin and PARP1 inhibitors (PARP1-Is). Independent of BRCA1/2 status, PARP1 expression dictated the degree of synergism. Namely, silenced PARP1 reduced trabectedin-PARP1-Is synergism, whereas overexpressed PARP1 increased combination efficacy. High-PARP1 expression and specific gene signatures associated with DNA damage response and repair (DDR-R) were predictive of trabectedin+PARP1-I synergy. These findings pave the way for the clinical development of this novel combination therapy, as well as evaluation of PARP1 expression and DDR-R signatures in tumor samples as predictive biomarkers of response

2017-06-12 | GSE77175 | GEO

PARP1 expression predicts and determines synergy between PARP1 inhibitors and trabectedin.

2017-06-12 | GSE76981 | GEO