Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.143 (poly(ADP-ribose) glycohydrolase)
 208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribosyl)ation is a unique post-translational modification of proteins. The metabolism of poly(ADP-ribose) (PAR) is tightly regulated mainly by poly(ADP-ribose) polymerases (PARP) and poly(ADP-ribose) glycohydrolase (PARG). Accumulating evidence has suggested the biological functions of PAR metabolism in control of many cellular processes, such as cell proliferation, differentiation and death by remodeling chromatin structure and regulation of DNA transaction, including DNA repair, replication, recombination and transcription. However, the physiological roles of the catabolism of PAR catalyzed by PARG remain less understood than those of PAR synthesis by PARP. Noteworthy biochemical studies have revealed the importance of PAR catabolic pathway generating nuclear ATP via the coordinated actions of PARG and ADP-ribose pyrophosphorylase (ADPRPPL) for the driving of DNA repair and the maintenance of DNA replication apparatus while repairing DNA damage. Furthermore, genetic studies have shown the value of PARG as a therapeutic molecular target for PAR-mediated diseases, such as cancer, inflammation and many pathological conditions. In this review, we present the current knowledge of de-poly(ADP-ribosyl)ation catalyzed by PARG focusing on its role in DNA repair, replication and apoptosis. Furthermore, the induction of apoptosis code of DNA replication catastrophe by synthetic lethality of PARG inhibition and the recent progresses regarding the development of small molecule PARG inhibitors and their therapeutic potentials in cancer chemotherapy are highlighted in this review.
 ...
PMID:Targeting poly(ADP-ribose) glycohydrolase to draw apoptosis codes in cancer. 3117 15

Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.
 ...
PMID:Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death. 3182 85

There is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are key enzymes in BER that elongate and degrade PAR polymers on target proteins. While PARP inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the PARG locus and induces PARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. Thus, AR and PARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients.
 ...
PMID:Androgen Receptor and Poly(ADP-ribose) Glycohydrolase Inhibition Increases Efficiency of Androgen Ablation in Prostate Cancer Cells. 3212 73

Poly(ADP-ribosyl)ation reactions constitute a post-translational protein modification synthesized in higher eukaryotes by a family of poly(ADP-ribose)polymerases (PARP) and catabolized mainly by poly(ADP-ribose) glycohydrolase (PARG). The best understood role of PARP is the maintenance of genomic integrity via the promotion of DNA repair that leads to cell survival when low levels of genotoxic stress occur. The participation of PARP in unleashing cell death at higher levels of damage has also been broadly studied. The biology of poly(ADP-ribosyl)ation in protozoan parasites, however, still remains a mystery. This review will examine the presence of the key enzyme involved in ADP-ribose polymer (PAR) metabolism in protozoan parasites associated with human diseases. Theoretical and experimental data obtained up to date have revealed the presence of PAR metabolism only in the trypanosomatids Trypanosoma cruzi and T. brucei, the apicomplexan Toxoplasma gondii and Entamoeba histolytica. T. cruzi and T. brucei, as opposed to humans and other organisms, have only one PARP and one PARG with subcellular localizations that are distinct from the ones described for their mammalian counterparts. The topics discussed in this review describe the first studies on PAR metabolism in trypanosomatids, specially the role of PAR on DNA damage response, cell cycle progression and cell death after genotoxic stimuli. The results described show differences in some aspects of PAR metabolism in trypanosomatids in comparison to other eukaryotes. New questions about the function of this metabolic pathway in the parasites under study are open and we hope it encourages the research community to explore this signaling pathway as a new possible target of clinical relevance in these and other disease-causing parasites.
 ...
PMID:Poly(ADP-ribose) metabolism in human parasitic protozoa. 3233 Apr 49

The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.
 ...
PMID:Regulation of ALT-associated homology-directed repair by polyADP-ribosylation. 3304 7


<< Previous 1 2 3 4 5