Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion Positive Prostate Cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Christopher Maher
PROVIDER: E-GEOD-27723 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.
Brenner J Chad JC Ateeq Bushra B Li Yong Y Yocum Anastasia K AK Cao Qi Q Asangani Irfan A IA Patel Sonam S Wang Xiaoju X Liang Hallie H Yu Jindan J Palanisamy Nallasivam N Siddiqui Javed J Yan Wei W Cao Xuhong X Mehra Rohit R Sabolch Aaron A Basrur Venkatesha V Lonigro Robert J RJ Yang Jun J Tomlins Scott A SA Maher Christopher A CA Elenitoba-Johnson Kojo S J KS Hussain Maha M Navone Nora M NM Pienta Kenneth J KJ Varambally Sooryanarayana S Feng Felix Y FY Chinnaiyan Arul M AM
Cancer cell 20110501 5
Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription ...[more]
Similar Datasets
Project description:To identify commonly altered genes between ERG, PARP1, and DNA-PKcs.
2011-05-18 | GSE27723 | GEO
Project description:Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
| S-EPMC3113473 | biostudies-literature
Project description:Poly (ADP-Ribose) Polymerase 1 (PARP1) is a ubiquitously expressed enzyme that regulates DNA damage repair, cell death, inflammation, and transcription. PARP1 functions by adding ADP-ribose polymers (PAR) to proteins including itself, using NAD+ as a donor. This post-translational modification known as PARylation results in changes in the activity of PARP1 and its substrate proteins and has been linked to the pathogenesis of various neurological diseases. PARP1 KO mice display schizophrenia-like behaviors, have impaired memory formation, and have defects in neuronal proliferation and survival, while mutations in genes that affect PARylation have been associated with intellectual disability, psychosis, neurodegeneration, and stroke in humans. Yet, the roles of PARP1 in brain development have not been extensively studied. We now find that loss of PARP1 leads to defects in brain development and increased neuronal density at birth. We further demonstrate that PARP1 loss increases the expression levels of genes associated with neuronal migration and adhesion in the E15.5 cerebral cortex, including Reln. This correlates with an increased number of Cajal-Retzius (CR) cells in vivo and in cultures of embryonic neural progenitor cells (NPCs) derived from the PARP1 KO cortex. Furthermore, PARP1 loss leads to increased NPC adhesion to N-cadherin, like that induced by experimental exposure to Reelin. Taken together, these results uncover a novel role for PARP1 in brain development, i.e., regulation of CR cells, neuronal density, and cell adhesion.
2021-09-16 | GSE171852 | GEO
Project description:Formation of a repair enzyme complex is beneficial to DNA repair. Despite cellular studies showed that mitochondrial DNA polymerase (Pol ) and poly(ADP-ribose) polymerase 1 (PARP1) were found in the same complex along with other mitochondrial DNA repair enzymes and mitochondrial PARP1 level is correlated with mtDNA integrity, the molecular basis for the functional connection between Pol and PARP1 has not been illustrated, because cellular functions of PARP1 in DNA repair are intertwined with metabolism via NAD+ (nicotinamide adenosine dinucleotide), the substrate of PARP1 and a metabolic cofactor. To dissect the direct effect of PARP1 on mtDNA from the secondary perturbation metabolism, we report here biochemical studies that recapitulated Pol PARylation observed in cells, showed that PARP1 regulates Pol activity during DNA repair in a metabolic cofactor NAD+ (nicotinamide adenosine dinucleotide)-dependent manner. In the absence of NAD+, PARP1 completely inhibits Pol, while increasing NAD+ level to physiological concentration enables Pol to resume maximum repair activity. Because cellular NAD+ levels are linked to metabolism and to ATP production via oxidative phosphorylation, our results suggest that mtDNA damage repair is correlated with cellular metabolic state and integrity of the respiratory chain.
2020-12-16 | MSV000086606 | MassIVE
Project description:Poly(ADP-ribose) polymerase 1 (PARP1) critically facilitates DNA damage response (DDR) that suppresses genomic instability. However, the physiological function of PARP1 in regulating genomic integrity is unclear. We investigated the Ewing’s sarcoma breakpoint region 1 (EWS) and found that it regulated the physiological function of PARP1. EWS was indispensable to dissociation of PARP1 from damaged DNA, promoting DDR and regulating DDR protein expression. Abnormal PARP1 accumulation due to EWS expression silencing, induced hyper-PARylation, which exhausted cellular NAD+ levels and caused cell death in in vitro and in vivo. Positively charged EWS arginine-glycine-glycine (Arg-Gly-Gly, RGG) domains directly interact with poly ADP-ribose (PAR) chains produced by PARP1 and are essential to dissociate PARP1 from damaged DNA. Consistently, Ewing’s sarcoma cells with defective EWS function accumulated PARP1 on chromatin and tissues from Ewing’s sarcoma patients, exhibiting high PARylation levels. Taken together, loss of EWS causes defects in PARP1 dissociation and results in genomic instability.
2020-11-03 | PXD016145 | Pride
Project description:Post-translational modifications, such as poly(ADP-ribosyl)ation (PARylation), regulate chromatin-modifying enzymes, ultimately affecting gene expression. This study explores the role of poly(ADP-ribose) polymerase (PARP) on global gene expression in a lymphoblastoid B cell line. We found that inhibition of PARP catalytic activity with olaparib resulted in global gene deregulation, affecting approximately 11% of genes expressed. Gene ontology analysis revealed that PARP could exert these effects through transcription factors and chromatin-remodeling enzymes, including the Polycomb Repressive Complex 2 (PRC2) member EZH2. EZH2 mediates the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification associated with chromatin compaction and gene silencing. Both pharmacological inhibition of PARP and knockdown of PARP1 induced the expression of EZH2 that resulted in increased global H3K27me3. Chromatin immunoprecipitation confirmed that PARP1 inhibition led to H3K27me3 deposition at EZH2-target genes, which resulted in gene silencing. Moreover, increased EZH2 expression is attributed to occupancy loss of the transcription repressor E2F4 at the EZH2 promoter following PARP inhibition. Together, these data show that PARP plays an important role in global gene regulation and identifies for the first time a direct role of PARP1 in regulating the expression and function of EZH2.
2015-11-13 | GSE74974 | GEO
Project description:Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein-Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro. Poly(ADP-ribose) polymerase 1 (PARP1) regulates accessibility of chromatin, alters functions of transcriptional activators and repressors, and has been directly implicated in transcriptional activation. Previously we showed that LMP1 activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. Therefore, to identify targets of LMP1 that are regulated through PARP1, LMP1 was ectopically expressed in an EBV-negative Burkitt’s lymphoma cell line. These LMP1-expressing cells were then treated with the PARP inhibitor olaparib and prepared for RNA sequencing. The LMP1/PARP targets identified through this RNA-seq experiment are largely involved in metabolism and signaling. Interestingly, Ingenuity Pathway Analysis of RNA-seq data suggests that hypoxia-inducible factor 1-alpha (HIF-1α) is an LMP1 target mediated through PARP1. PARP1 is acting as a coactivator of HIF-1α-dependent gene expression in B cells, and this co-activation is enhanced by LMP1-mediated activation of PARP1. HIF-1α forms a PARylated complex with PARP1 and both HIF-1α and PARP1 are present at promoter regions of HIF-1α downstream targets, leading to accumulation of positive histone marks at these regions. Complex formation, PARylation and binding of PARP1 and HIF-1α at promoter regions of HIF-1α downstream targets can all be attenuated by PARP1 inhibition, subsequently leading to a buildup of repressive histone marks and loss of positive histone marks. In addition, LMP1 switches cells to a glycolytic ‘Warburg’ metabolism, preferentially using aerobic glycolysis over mitochondrial respiration. Finally, LMP1+ cells are more sensitive to PARP1 inhibition and, therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies.
2018-10-24 | GSE121476 | GEO
Project description:Veliparib showed limited single agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin and etoposide in vitro in 5 of 9 SCLC cell lines. Veliparib with cisplatin, etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC=0.672; p=0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2 and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
2014-12-31 | GSE55830 | GEO
Project description:Poly(ADP-ribose) (pADPr) is a polymer assembled from the enzymatic polymerization of the ADP-ribosyl moiety of NAD by poly(ADP-ribose) polymerases (PARPs). The dynamic turnover of pADPr within the cell is essential for a number of cellular processes including progression through the cell cycle, DNA repair and the maintenance of genomic integrity, and apoptosis. In spite of the considerable advances in the knowledge of the physiological conditions modulated by poly(ADP-ribosyl)ation reactions, and notwithstanding the fact that pADPr can play a role of mediator in a wide spectrum of biological processes, few pADPr binding proteins have been identified so far. In this study, refined in silico prediction of pADPr binding proteins and large-scale mass spectrometry-based proteome analysis of pADPr binding proteins were used to establish a comprehensive repertoire of pADPr-associated proteins. Visualization and modeling of these pADPr-associated proteins in networks not only reflect the widespread involvement of poly(ADP-ribosyl)ation in several pathways but also identify protein targets that could shed new light on the regulatory functions of pADPr in normal physiological conditions as well as after exposure to genotoxic stimuli.
| S-EPMC2602769 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase 3 (PARP3) is a member of the PARP family of enzymes. It is structurally related to the well characterized type member PARP1 that orchestrates DNA strand break repair and cell death by the synthesis of poly(ADP-ribose). In contrast, the functions of PARP3 are undefined. We have used several in vitro and in vivo approaches to examine the possible functions of PARP3 as a transcriptional regulator, a function suggested from its previously reported association with several Polycomb group (PcG) proteins. A ChIP-chip analysis of PARP3 gene occupancy in the human neuroblastoma cell line SK-N-SH reveals that PARP3 is preferentially associated with developmental genes and is significantly enriched around the transcriptional start site of several genes encoding neuronal and sensory placodes specifiers, such as SOX9, DLX3 and DLX4. Using zebrafish as a vertebrate animal model, we demonstrate that Parp3 plays a key role in ectodermal and neural crest specification. Morpholino oligonucleotide-directed inhibition of parp3 expression in zebrafish impairs the expression of the neural crest cell specifier sox9a and of dlx3b/dlx4b, the formation of cranial sensory placodes, inner ears and pectoral fins. It delays pigmentation and severely impedes the development of the median fin fold and tail bud. Our findings demonstrate that Parp3 is crucial in the early stages of zebrafish development, possibly by exerting its transcriptional regulatory functions as early as during the specification of the neural plate border. ChIP were conducted as described (Rodrigue et al. 2006). PARP3 was immunoprecipitated from 3 x 10^7 SK-N-SH cells with a commercial anti-PARP3 (Enzo Life Sciences ALX-210-541). In control ChIP, PARP3 antibodies were replaced by rabbit IgG. Two independent PARP3 and control ChIP-chip experiments were achieved. The DNA was amplified using LM-PCR and labelled with Cy5 (PARP3) and Cy3 (IgG) before hybridization on Agilent Human promoter arrays (two 244k chip per ChIP for a total of 4 chips). Detailed protocols can be found at http://www.ircm.qc.ca/microsites/francoisrobert/en. Regions significantly enriched for PARP3 relative to IgG were identified as described (Lee et al. 2006).
2011-08-17 | E-GEOD-23709 | biostudies-arrayexpress