Poly(ADP-ribose) polymerase 1 (PARP-1) binds to 8-oxoguanine-DNA glycosylase (OGG1).
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ABSTRACT:
SUBMITTER: Noren Hooten N
PROVIDER: S-EPMC3247967 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP inhibitors and ionizing radiation. Researchers have determined the efficacy of various PARP inhibitors at sub-cytotoxic concentrations in radiosensitizing multiple human cancer cell lines to ionizing radiation. Furthermore, several groups have begun evaluating combination therapy strategies in mouse models of cancer, and a fluorescent imaging agent that allows for subcellular imaging in real time has been developed from a PARP inhibitor scaffold. Other PARP inhibitor scaffolds have been radiolabeled to create PET imaging agents, some of which have also entered clinical trials. Most recently, these highly targeted small molecules have been radiolabeled with therapeutic isotopes to create radiotherapeutics and radiotheranostics in cancers whose primary interventions are surgical resection and whole-body radiotherapy. In this review we discuss the utilization of these small molecules in combination therapies and in scaffolds for imaging agents, radiotherapeutics, and radiotheranostics. Development of these radiolabeled PARP inhibitors has presented promising results for new interventions in the fight against some of the most intractable cancers.
| S-EPMC7062869 | biostudies-literature
Project description:PARP-1 is involved in multiple cellular processes, including transcription, DNA repair, and apoptosis. PARP-1 attaches ADP-ribose units to target proteins, including itself as a post-translational modification that can change the biochemical properties of target proteins and mediate recruitment of proteins to sites of poly(ADP-ribose) synthesis. Independent of its catalytic activity, PARP-1 binds to chromatin and promotes compaction affecting RNA polymerase II transcription. PARP-1 has a modular structure composed of six independent domains. Two homologous zinc fingers, Zn1 and Zn2, form the DNA-binding module. Zn1-Zn2 binding to DNA breaks triggers catalytic activity. Recently, we have identified a third zinc binding domain in PARP-1, the Zn3 domain, which is essential for DNA-dependent PARP-1 activity. The crystal structure of the Zn3 domain revealed a novel zinc-ribbon fold and a homodimeric Zn3 structure that formed in the crystal lattice. Structure-guided mutagenesis was used here to investigate the roles of these two features of the Zn3 domain. Our results indicate that the zinc-ribbon fold of the Zn3 domain mediates an interdomain contact crucial to assembly of the DNA-activated conformation of PARP-1. In contrast, residues located at the Zn3 dimer interface are not required for DNA-dependent activation but rather make important contributions to the chromatin compaction activity of PARP-1. Thus, the Zn3 domain has dual roles in regulating the functions of PARP-1.
| S-EPMC2881810 | biostudies-literature
Project description:Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health.
| S-EPMC2800114 | biostudies-literature
Project description:BackgroundOvarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has spread throughout the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy.PARP (poly (ADP-ribose) polymerase) inhibitors, are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer, with respect to survival, side effects and quality of life.ObjectivesTo determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer (EOC).Search methodsWe identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to May 2014), EMBASE (1990 to May 2014), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.Selection criteriaWomen with histologically proven EOC who were randomised to treatment groups in trials that either compared PARP inhibitors with no treatment, or PARP inhibitors versus conventional chemotherapy, or PARP inhibitors together with conventional chemotherapy versus conventional chemotherapy alone.Data collection and analysisWe used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data, where possible. Outcomes included survival, quality of life and toxicity.Main resultsWe included four RCTs involving 599 women with EOC. Data for veliparib were limited and of low quality, due to small numbers (75 women total). Olaparib, on average, improved progression-free survival (PFS) when added to conventional treatment and when used as maintenance treatment in women with platinum-sensitive disease compared with placebo (hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.29 to 0.60; 426 participants ; two studies), but did not improve overall survival (OS) (HR 1.05, 95% CI 0.79 to 1.39; 426 participants; two studies). We graded this evidence as moderate quality using the GRADE approach. Olaparib was associated with more severe adverse events (G3/4) during the maintenance phase compared with controls (risk ratio (RR) 1.74, 95% CI 1.22 to 2.49; 385 participants, two studies; moderate quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies.Authors' conclusionsPARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease. Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC. More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease.
| S-EPMC6457589 | biostudies-literature
Project description: Not available
| S-EPMC8848772 | biostudies-literature
Project description:Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.
| S-EPMC9736565 | biostudies-literature
Project description:The DNA base excision repair (BER) pathway, which utilizes DNA glycosylases to initiate repair of specific DNA lesions, is the major pathway for the repair of DNA damage induced by oxidation, alkylation, and deamination. Early results from clinical trials suggest that inhibiting certain enzymes in the BER pathway can be a useful anticancer strategy when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. Despite this general validation of BER enzymes as drug targets, there are many enzymes that function in the BER pathway that have few, if any, specific inhibitors. There is a growing body of evidence that suggests inhibition of 8-oxoguanine DNA glycosylase-1 (OGG1) could be useful as a monotherapy or in combination therapy to treat certain types of cancer. To identify inhibitors of OGG1, a fluorescence-based screen was developed to analyze OGG1 activity in a high-throughput manner. From a primary screen of ∼50,000 molecules, 13 inhibitors were identified, 12 of which were hydrazides or acyl hydrazones. Five inhibitors with an IC50 value of less than 1 μM were chosen for further experimentation and verified using two additional biochemical assays. None of the five OGG1 inhibitors reduced DNA binding of OGG1 to a 7,8-dihydro-8-oxoguanine (8-oxo-Gua)-containing substrate, but all five inhibited Schiff base formation during OGG1-mediated catalysis. All of these inhibitors displayed a >100-fold selectivity for OGG1 relative to several other DNA glycosylases involved in repair of oxidatively damaged bases. These inhibitors represent the most potent and selective OGG1 inhibitors identified to date.
| S-EPMC4894821 | biostudies-literature
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.
| S-EPMC4606886 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase 1 (PARP1), a nuclear protein, utilizes NAD to synthesize poly(AD-Pribose) (pADPr), resulting in both automodification and the modification of acceptor proteins. Substantial amounts of PARP1 and pADPr (up to 50%) are localized to the nucleolus, a subnuclear organelle known as a region for ribosome biogenesis and maturation. At present, the functional significance of PARP1 protein inside the nucleolus remains unclear. Using PARP1 mutants, we investigated the function of PARP1, pADPr, and PARP1-interacting proteins in the maintenance of nucleolus structure and functions. Our analysis shows that disruption of PARP1 enzymatic activity caused nucleolar disintegration and aberrant localization of nucleolar-specific proteins. Additionally, PARP1 mutants have increased accumulation of rRNA intermediates and a decrease in ribosome levels. Together, our data suggests that PARP1 enzymatic activity is required for targeting nucleolar proteins to the proximity of precursor rRNA; hence, PARP1 controls precursor rRNA processing, post-transcriptional modification, and pre-ribosome assembly. Based on these findings, we propose a model that explains how PARP1 activity impacts nucleolar functions and, consequently, ribosomal biogenesis.
| S-EPMC3252306 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
| S-EPMC7470090 | biostudies-literature