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PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

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: GSE77175 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA309661

REPOSITORIES: GEO

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

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 | GSE76981 | 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

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

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

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

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 | GSE55485 | GEO

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

2015-06-04 | GSE55484 | 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

Whole-genome landscape PARP1 in HEK293T cells

Project description:Poly [ADP-ribose] polymerase 1 (PARP1) is involved in differentiation, proliferation, tumor transformation, in repair of single-stranded DNA and double-stranded DNA breaks (DSBs) in conjunction with BRCA. PARP1 enzyme works modifying nuclear proteins by poly ADP-ribosylation. It was found that PARP1 and HNRNPA2B1 bind at termini of forum domains and may play a role in coordinated regulation of genes in forum domains (Tchurikov et al., 2013). Forum domains are long DNA fragments of excised chromosomal DNA. Mostly forum domains are of 50-200 kb in length, although larger domains, up to 500 - 700 kb, are also observed. The domains are delimited by hot spots of double-strand breaks (DSBs). This ChIP-Seq is aimed to compare genome-wide binding sites of PARP1 with different genomic features, including the hot spots of DSBs.

2017-02-01 | GSE74954 | GEO

Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells

Project description:Genomic instability is one of the hallmarks of cancer. Several chemotherapeutic drugs and radiotherapy induce DNA damage to prevent cancer cell replication. Cells in turn activate different DNA damage response (DDR) pathways to either repair the damage or induce cell death. These DDR pathways also elicit metabolic alterations which can play a significant role in the proper functioning of the cells. The understanding of these metabolic effects resulting from different types of DNA damage and repair mechanisms is currently lacking. In this study, we used NMR metabolomics to identify metabolic pathways which are altered in response to different DNA damaging agents. By comparing the metabolic responses in MCF-7 cells, we identified the activation of poly (ADP-ribose) polymerase (PARP) in methyl methanesulfonate (MMS)-induced DNA damage. PARP activation led to a significant depletion of NAD+. PARP inhibition using veliparib (ABT-888) was able to successfully restore the NAD+ levels in MMS-treated cells. In addition, double strand break induction by MMS and veliparib exhibited similar metabolic responses as zeocin, suggesting an application of metabolomics to classify the types of DNA damage responses. This prediction was validated by studying the metabolic responses elicited by radiation. Our findings indicate that cancer cell metabolic responses depend on the type of DNA damage responses and can also be used to classify the type of DNA damage.

2015-08-01 | MTBLS177 | MetaboLights

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