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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76981 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA309170

REPOSITORIES: GEO

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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 proximity proteomics reveals interaction partners at stressed replication forks

Project description:PARP1 mediates poly-ADP-ribosylation of proteins on chromatin in response to different types of DNA lesions. PARP inhibitors are used for the treatment of BRCA1/2-deficient breast, ovarian, and prostate cancer. Loss of DNA replication fork protection is proposed as one mechanism that contributes to the vulnerability of BRCA1/2-deficient cells to PARP inhibitors. However, the mechanisms that regulate PARP1 activity at stressed replication forks remain poorly understood. Here, we performed proximity proteomics of PARP1 and isolation of proteins on stressed replication forks to map putative PARP1 regulators. We identified TPX2 as a direct PARP1-binding protein that regulates the auto-ADP-ribosylation activity of PARP1. TPX2 interacts with DNA damage response proteins and promotes homology-directed repair of DNA double-strand breaks. Moreover, TPX2 mRNA levels are increased in BRCA1/2-mutated breast and prostate cancers, and high TPX2 expression levels correlate with the sensitivity of cancer cells to PARP-trapping inhibitors. We propose that TPX2 confers a mitosis-independent function in the cellular response to replication stress by interacting with PARP1.

2022-10-11 | PXD037154 | Pride

EZH2 directly methylates PARP1 and regulates its activity in cancer

Project description:DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair pathways and their dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly (ADP-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, at lysine 607 and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, inhibits the recruitment of X-ray repair cross-complementing group-1 (XRCC1) recruitment to DNA lesions and hence impairs DNA damage repair. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. Collectively, our findings uncover a novel insight of EZH2 functions in DNA damage repair and cancer progression, which provides a new rationale for combinational targeting EZH2 and PARP1 in cancer.

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Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Project description:Recent studies have highlighted the critical role of metabolism in the response to DNA damage. However, the precise metabolic interactions that are set in motion to tune this fundamental process remain largely unknown. In this study, we investigated the role of nuclear metabolism in the DNA damage response using triple-negative breast cancer as a model. By comparing the chromatin-associated proteome of different breast cancer subtypes, we observed that the purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched in the chromatin of triple-negative breast cancer cells, which are often prone to DNA damage accumulation. Downregulation, depletion, or inhibition of IMPDH2 leads to accumulation of DNA damage. IMPDH2 chromatin localization is DNA damage dose dependent and happens at a late stage of the DNA damage repair. On chromatin, IMPDH2 interacts with PARP1. The enzymatic function of IMPDH2, which consumes NAD+, modulates PARP1 activity, thus mediating a pondered DNA damage response. However, forcing the nuclear localization of exogenous IMPDH2 provokes a dramatic NAD+ depletion that results in PARP1 cleavage and consequent cytoplasmic translocation, which mediates apoptosis. Our study identifies a moonlighting role for IMPDH2 in the control of nuclear ATP and NAD+ level, which fine-tune the activation of PARP1 and regulates the DNA damage response.

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Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition

Project description:Although pre-clinical and clinical studies on PARP1 inhibitors, alone and in combination with DNA-damaging agents, show promising results, further ways to improve and broaden the scope of application of this therapeutic approach are warranted. To this end, we have investigated the possibility of improving the response of BRCA1 mutant breast cancer cells to PARP1 inhibition by co-targeting the PI3K pathway. The human breast cancer cell line MDA-MB-436, which lacks the expression of both BRCA1 and PTEN, was treated with the PARP1 inhibitor AG014699 as a single agent or in combination with the PI3K inhibitor LY294002 for 7 days. The human breast cancer cell line MDA-MB-436 was treated with the PARP1 inhibitor AG014699 as a single agent or in combination with the PI3K inhibitor LY294002 for 7 days. All treatments were performed in triplicates. Total RNA was extracted hybridized onto the Illumina HumanHT-12 v4.0 microarray platform.

2012-01-19 | E-GEOD-34817 | biostudies-arrayexpress

Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition

2012-01-19 | GSE34817 | GEO

Defective Mitophagy in XPA via PARP1 activation and NAD+/SIRT1-depletion: Implications for neurodegeneration (human)

Project description:Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP1. This phenotype is rescued by PARP1 inhibition or by supplementation with NAD+ precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a novel nuclear-mitochondrial cross-talk that is critical for the maintenance of mitochondrial health.

2015-06-04 | GSE55484 | GEO

Defective Mitophagy in XPA via PARP1 activation and NAD+/SIRT1-depletion: Implications for neurodegeneration (mouse)

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Identification of diffrentially expressed genes upon DDSR1 knockdown

Project description:Upon DNA damage, the DNA damage response (DDR) elicits a complex signaling cascade, which includes the induction of multiple non-coding RNA species. Recently long non-coding RNAs (lncRNAs) have been shown to contribute to DDR by regulating gene expression. However, very little is known about the role that lncRNAs play in regulating DNA Repair. Using a genome-wide microarray screen we identified a novel ubiquitously expressed lncRNA, DDSR1 (DNA damage-sensitive RNA 1), which is induced upon DNA damage by several DNA double-strand break (DSB) agents. DDSR1 induction upon DNA damage is dependent on the ATM-NF-kB pathway but p53 independent. However, DDSR1 acts in the p53 network by negatively regulating p53 mediated gene expression. Loss of DDSR1 impairs cell proliferation, DDR signaling and reduces DNA repair capacity by homologous recombination (HR). The HR defect upon DDSR1 knockdown is due to reduced end resection caused by aberrant BRCA1 and RAP80 accumulation at DSB sites. In line with dual role of DDSR1 in gene regulation and HR, DDSR1 interacts with hnRNPUL1, an RNA-binding protein involved in transcription and HR. Our results reveal a previously unknown lncRNA involved in regulation of DDR by contributing to gene regulation and DNA repair by HR. Our findings highlight the importance of DDSR1 in maintaining genome stability and suggest that the DDR is even more complex than currently assumed. We used microarrays to identify gene expression changes upon DDSR1 knockdown

2015-09-01 | GSE67048 | GEO

PARP1 gene knockout suppresses expression of DNA Base Excision Repair genes

Project description:PARP1 is a member of various DNA repair pathways - main target for anti-cancer treatment. We evaluated the effect of topotecan and TDP1 Inhibitor in HEK293 wild-type and PARP1 knockout cells on the gene expression

2022-12-01 | GSE218871 | GEO

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