Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diethyldithiocarbamate (DDTC) has been shown to induce cytotoxicity in several different systems. We examined whether the DDTC-induced cytotoxicity was via apoptosis, or in relation to intracellular glutathione (GSH) in various murine and human leukemia cell lines. The cells most sensitive to DDTC-induced cytotoxicity were P388 lymphoid neoplasma cells and NALM-6, a B cell line of acute lymphocytic leukemia (ALL). The next level of susceptible cells included J774.1, having a macrophage function, HL-60 premyelocytic leukemia cells, MOLT-4, an acute lymphoblastic leukemia cell, and Jurkat, a T-cell leukemia. U937 (expressing many monocyte-like characteristics), K562 erythroleukemia and K562/DXR (a multidrug-resistant clone derived from K562) were almost unaffected by DDTC. P388 was also highly susceptible to H(2)O(2), a most useful exogenous reactive oxygen species generator, and was lower in intracellular total GSH content than other leukemia cells. DDTC-induced cytotoxicity was closely related to intracellular GSH, but the level of cellular GSH did not always correlate with H(2)O(2)-induced cytotoxicity in this experiment. K562 had a higher intracellular total GSH content and showed lower susceptibility to DDTC and H(2)O(2), but with the combination of DDTC and DL-buthionine-(S,R)-sulfoximine (BSO), cytotoxicity increased significantly. The ratio of GSH/GSSG in P388 was reduced by DDTC or H(2)O(2). H(2)O(2)-induced cytotoxicity was completely blocked by catalase (CAT), while it was enhanced by superoxide dismutase (SOD). CAT or SOD did not affect DDTC-induced cytotoxicity. N-Acetylcysteine (NAC: 1 mM), a vanguard substance of GSH, and aurintricarboxylic acid (ATA: 100 microM), an endonuclease inhibitor, ameliorated DDTC-induced cytotoxicity and apoptosis. In conclusion, we suggest that DDTC-induced cytotoxicity was via an oxidative shift in the intracellular redox state, and accompanied the activation of endonuclease through apoptosis in leukemia cell lines.
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PMID:Diethyldithiocarbamate-induced cytotoxicity and apoptosis in leukemia cell lines. 1284 19

The Arabidopsis sog1-1 (suppressor of gamma response) mutant was originally isolated as a second-site suppressor of the radiosensitive phenotype of seeds defective in the repair endonuclease XPF. Here, we report that SOG1 encodes a putative transcription factor. This gene is a member of the NAC domain [petunia NAM (no apical meristem) and Arabidopsis ATAF1, 2 and CUC2] family (a family of proteins unique to land plants). Hundreds of genes are normally up-regulated in Arabidopsis within an hour of treatment with ionizing radiation; the induction of these genes requires the damage response protein kinase ATM, but not the related kinase ATR. Here, we find that SOG1 is also required for this transcriptional up-regulation. In contrast, the SOG1-dependent checkpoint response observed in xpf mutant seeds requires ATR, but does not require ATM. Thus, phenotype of the sog1-1 mutant mimics aspects of the phenotypes of both atr and atm mutants in Arabidopsis, suggesting that SOG1 participates in pathways governed by both of these sensor kinases. We propose that, in plants, signals related to genomic stress are processed through a single, central transcription factor, SOG1.
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PMID:Suppressor of gamma response 1 (SOG1) encodes a putative transcription factor governing multiple responses to DNA damage. 1954 33

The families of the plant-specific transcription factors (TFs) are defined by their characteristic DNA-binding domains (DBDs), such as AP2/ERF, B3, NAC, SBP, and WRKY. Recently, three-dimensional structures of the DBDs, including those in complexes with DNA, were determined by NMR spectroscopy and X-ray crystallography. In this review we summarize the functional and evolutionary implications arising from structure analyses. The unexpected structural similarity between B3 and the noncatalytic DBD of the restriction endonuclease EcoRII allowed us to build structural models of the B3/DNA complex. Most of the DBDs of plant-specific TFs are likely to have originated from endonucleases associated with transposable elements. After the DBDs have been established in unicellular eukaryotes, they experienced extensive plant-specific expansion, by acquiring new functions.
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PMID:DNA-binding domains of plant-specific transcription factors: structure, function, and evolution. 2304 85

Cold storage of kidneys before transplantation is problematic because of the limited survival time of the allografts. In this study, zinc-N-acetylcysteine (ZnNAC) was shown to be a potent endonuclease inhibitor and antioxidant, and it was tested as a potential additive to a cold storage solution for kidney preservation. Exposure of normal rat kidney NRK-52E cells to ZnNAC resulted in zinc delivery to the cells as determined by TFL-Zn fluorophore and partial protection of the cells against injury by cold storage in University of Wisconsin solution (UWS) as measured by propidium iodide assay. Ex vivo, rat kidneys demonstrated time- and temperature-dependent DNA fragmentation as assessed by TUNEL assay, indicating irreversible cell death. DNA fragmentation was faster in the medulla than in the cortex, and tubules were affected more than glomeruli. Perfusion of rat kidneys with cold ZnNAC solution in UWS significantly inhibited cell death both in the cortex and medulla at concentrations of 0.3-30 mM compared with UWS alone, with a maximum effect at 1-10 mM ZnNAC. Cold storage of the kidney significantly increased quantities of cleaved caspase-3 and endonuclease G (EndoG) in the tissue, which were abolished by 10 mM ZnNAC, indicating its ability to suppress both caspase-dependent and -independent cell death. Therefore, supplementation of UWS with ZnNAC can decrease DNA fragmentation and protect kidney allografts from cell death due to cold storage.
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PMID:Protective effect of zinc-N-acetylcysteine on the rat kidney during cold storage. 2382 76

Despite the fact that alveolar macrophages play an important role in smoking-related disease, little is known about what regulates their pathophysiologic phenotype. Evaluating smoker macrophages, we found significant down-regulation of multiple microRNAs (miRNAs). This work investigates the hypothesis that cigarette smoke alters mature miRNA expression in lung macrophages by inhibiting processing of primary miRNA transcripts. Studies on smoker alveolar macrophages showed a defect in miRNA maturation. Studies on the miRNA biogenesis machinery led us to focus on the cytosolic RNA endonuclease, DICER. DICER cleaves the stem-loop structure from pre-miRNAs, allowing them to dissociate into their mature 20-22-nucleotide single-stranded form. DICER activity assays confirmed impaired DICER activity following cigarette smoke exposure. Further protein studies demonstrated a decreased expression of the native 217-kDa form of DICER and an accumulation of high molecular weight forms with cigarette smoke exposure. This molecular mass shift was shown to contain SUMO moieties and could be blocked by silencing RNA directed at the primary SUMOylating ligase, Ubc9. In determining the cigarette smoke components responsible for changes in DICER, we found that N-acetylcysteine, an antioxidant and anti-aldehyde, protected DICER protein and activity from cigarette smoke extract. This massive down-regulation of miRNAs (driven in part by alterations in DICER) may be an important regulator of the disease-promoting macrophage phenotype found in the lungs of smokers.
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PMID:A microRNA processing defect in smokers' macrophages is linked to SUMOylation of the endonuclease DICER. 2466 3


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