Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirteen interferon (IFN)-alpha functional genes have been reported. Among these, a number of genes have allelic members (variants). In the case of IFN-alpha17, five variants, IFN-alpha17a, IFN-alpha17b, IFN-alpha17c, IFN-alpha17d, and IFN-alphaT, are known. The variants differ from each other by base changes in the coding region, leading to differences in amino acid sequences. We have developed oligonucleotide primers for amplification of IFN-alpha17 gene(s) using polymerase chain reaction (PCR). Genomic DNA, obtained from over 28,000 normal healthy individuals and from four cell lines, were used as templates in PCR to amplify the IFN-alpha17 gene sequences. The resulting PCR products were analyzed by restriction endonuclease digestion and DNA sequencing to identify the presence of variant sequences. The results show that a new variant of IFN-alpha17 is abundantly present (approximately 70%) along with another variant, possibly IFN-alpha17c (approximately 30%), in the genomic DNA of the population examined. This new variant, the protein product of which is identical to IFN-alpha17b, differs from the gene for IFN-alpha17b by a point mutation. We have named it IFN-alpha17b', which is the only variant found in U-937, KG-1, and EB-3 cell lines. Namalwa cells have IFN-alpha17b' and, possibly, IFN-alpha17c in equal proportions.
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PMID:A new allele of interferon-alpha17 gene encoding IFN-alpha17b is the major variant in human population. 971 62

RNase L is a latent endonuclease found in reptiles, birds, and mammals. It is activated by the 2',5'-phosphodiester-linked oligoadenylates called 2-5A and has been implicated in the mechanism of action of interferon, as well as in a variety of other biological phenomena such as apoptosis. Covalent linkage of 2-5A to antisense oligonucleotides permits recruitment of RNase L for enhancement of antisense action. The purification of RNase L described herein and the assays for its detection and activation will help to provide further mechanistic details on how this unique nuclease functions and what its biochemical roles may be. In addition, such assays will facilitate the screening of 2-5A-antisense congeners for exploration of the potential therapeutic applications of RNase L.
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PMID:Ribonuclease L, a 2-5A-dependent enzyme: purification to homogeneity and assays for 2-5A binding and catalytic activity. 973 9

The mammalian 2'-5' oligoadenylate synthetases (2'-5'OASs) are enzymes that are crucial in the interferon-induced antiviral response. They catalyze the polymerization of ATP into 2'-5'-linked oligoadenylates which activate a constitutively expressed latent endonuclease, RNaseL, to block viral replication at the level of mRNA degradation. A molecular evolutionary analysis of available OAS sequences suggests that the vertebrate genes are members of a multigene family with its roots in the early history of tetrapods. The modern mammalian 2'-5'OAS genes underwent successive gene duplication events resulting in three size classes of enzymes, containing one, two, or three homologous domains. Expansion of the OAS gene family occurred by whole-gene duplications to increase gene content and by domain couplings to produce the multidomain genes. Evolutionary analyses show that the 2'-5'OAS genes in rodents underwent gene duplications as recently as 11 MYA and predict the existence of additional undiscovered OAS genes in mammals.
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PMID:Expansion and molecular evolution of the interferon-induced 2'-5' oligoadenylate synthetase gene family. 1077 34

Thirteen interferon (IFN)-alpha functional genes have been reported. A number of these genes have allelic members (variants). In the case of IFN-alpha1, two variants, IFN-alpha1a and IFN-alpha1b, are known. The variants differ from each other by one base change in the coding region, leading to a single change in amino acid sequence and the presence of a restriction site. We have developed oligonucleotide primers for amplification of IFN-alpha1 gene(s) using polymerase chain reaction (PCR). Genomic DNA, obtained from over 23,000 normal healthy individuals and from four human cell lines, were used as templates in PCR to amplify the IFN-alpha1 gene sequences. The resulting PCR products were analyzed by restriction endonuclease digestion and DNA sequencing to identify the presence of variant sequences. The results show that IFN-alpha1a is predominant in the genomic DNA of the population examined. Among the cell lines studied, IFN-alpha1a is the only variant found in U-937 and Namalwa cells, whereas KG-1 cells have only IFN-alpha1b, and EB-3 cells have both IFN-alpha1a and IFN-alpha1b in the genome.
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PMID:IFN-alpha1a gene is the major variant in the North American population. 1103 95

The intracellular pathogen, Salmonella enterica serovar Typhimurium, is able to proliferate in phagocytes, although reactive oxygen and nitrogen intermediates are lethal to most phagocytosed bacteria. To determine whether repair of oxidatively damaged DNA is involved in S. typhimurium intramacrophage proliferation, null mutants of the DNA base excision repair (BER) system were generated. These mutants were deficient in discrete enzymes (Deltanth, Deltanei, Deltaxth, Deltanfo) or in the defined glycosylase (Deltanth/nei) and endonuclease (Deltaxth/nfo) steps. In this study, S. typhimurium BER mutants are characterized for the first time. In vitro characterization of the Salmonella BER mutants revealed phenotypes that are mostly consistent with characterized Escherichia coli BER mutants. These strains were used to evaluate the role of BER in the context of Salmonella virulence. S. typhimurium Deltaxth and Deltaxth/nfo were significantly impaired for survival in both cultured and primary macrophages activated with interferon (IFN)-gamma. Survival of Deltaxth and Deltaxth/nfo was improved nearly to wild-type levels in activated primary macrophages lacking both phagocyte oxidase and inducible nitric oxide synthase. In the murine typhoid fever model, Deltanth/nei was fivefold attenuated and Deltaxth/nfo was 12-fold attenuated compared with wild type. These data indicate that DNA oxidation is a mechanism that macrophages use to damage intracellular Salmonella, and suggest that BER-mediated repair of this damage may be important in the establishment of Salmonella infection. We speculate that adaptation to a pathogenic lifestyle may influence the acquisition and retention of redundant BER enzymes.
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PMID:The role of DNA base excision repair in the pathogenesis of Salmonella enterica serovar Typhimurium. 1267 11

RNA interference (RNAi) is the process of sequence-specific post-transcriptional gene silencing triggered by double-stranded RNAs. In attempts to identify RNAi triggers that effectively function at lower concentrations, we found that synthetic RNA duplexes 25-30 nucleotides in length can be up to 100-fold more potent than corresponding conventional 21-mer small interfering RNAs (siRNAs). Some sites that are refractory to silencing by 21-mer siRNAs can be effectively targeted by 27-mer duplexes, with silencing lasting up to 10 d. Notably, the 27-mers do not induce interferon or activate protein kinase R (PKR). The enhanced potency of the longer duplexes is attributed to the fact that they are substrates of the Dicer endonuclease, directly linking the production of siRNAs to incorporation in the RNA-induced silencing complex. These results provide an alternative strategy for eliciting RNAi-mediated target cleavage using low concentrations of synthetic RNA as substrates for cellular Dicer-mediated cleavage.
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PMID:Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. 1569 44

Developmentally aged chicken embryo cells which hyperproduce interferon (IFN) when induced were used to quantify IFN production and its suppression by eight strains of type A influenza viruses (AIV). Over 90% of the IFN-inducing or IFN induction-suppressing activity of AIV populations resided in noninfectious particles. The IFN-inducer moiety of AIV appears to preexist in, or be generated by, virions termed IFN-inducing particles (IFP) and was detectable under conditions in which a single molecule of double-stranded RNA introduced into a cell via endocytosis induced IFN, whereas single-stranded RNA did not. Some AIV strains suppressed IFN production, an activity that resided in a noninfectious virion termed an IFN induction-suppressing particle (ISP). The ISP phenotype was dominant over the IFP phenotype. Strains of AIV varied 100-fold in their capacity to induce IFN. AIV genetically compromised in NS1 expression induced about 20 times more IFN than NS1-competent parental strains. UV irradiation further enhanced the IFN-inducing capacity of AIV up to 100-fold, converting ISP into IFP and IFP into more efficient IFP. AIV is known to prevent IFN induction and/or production by expressing NS1 from a small UV target (gene NS). Evidence is presented for an additional downregulator of IFN production, identified as a large UV target postulated to consist of AIV polymerase genes PB1 + PB2 + PA, through the ensuing action of their cap-snatching endonuclease on pre-IFN-mRNA. The products of both the small and large UV targets act in concert to regulate IFN induction and/or production. Knowledge of the IFP/ISP phenotype may be useful in the development of attenuated AIV strains that maximally induce cytokines favorable to the immune response.
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PMID:Interferon induction and/or production and its suppression by influenza A viruses. 1570 7

In an avian flu pandemic, which drugs could be used to treat or prevent infection with influenza A (H5N1) virus? Foremost are the viral neuraminidase inhibitors oseltamivir and zanamivir, which have already been used to treat human influenza A (H1N1 and H3N2) and B virus infections. The use of the M2 ion channel blockers amantadine and rimantadine is compounded by the rapid development of drug resistance. Although formally approved for other indications (i.e. treatment of hepatitis C), ribavirin and pegylated interferon might also be useful for controlling avian flu. Combined use of the currently available drugs should be taken into account and attempts should be made to develop new strategies directed at unexplored targets such as the viral proteins hemagglutinin, the viral polymerase (and endonuclease) and the non-structural protein NS1. As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1.
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PMID:Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention. 1748 39

DNase II is an endonuclease which plays a fundamental role in the degradation of DNA from both apoptotic cells, and nuclei extruded from red blood cells during erythropoiesis: important tasks, considering that everyday 10(8)-10(9) cells undergo apoptosis, and 10(11) red blood cells are produced in the adult human. The DNase II-null mouse demonstrates embryonic lethality due to type I interferon-mediated erythroid precursor cell death triggered by undegraded nucleic acids. However, the mechanisms leading to such cytotoxicity are poorly understood. A study in the current issue of the European Journal of Immunology investigates the role of the death ligand TRAIL in this process. Although TRAIL is shown to be dispensable for the interferon-induced apoptosis of erythroid cells in DNAse II(-/-) embryos, the authors have developed a useful strategy for further exploring this question in future studies. Interestingly, earlier studies by the same group showed that crossing the DNase II-null mouse with a mouse deficient for the type I interferon receptor can rescue the lethal anaemia observed in the DNase II-null embryos, but only at the cost of developing autoimmunity.
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PMID:The story of DNase II: a stifled death-wish leads to self-harm. 2070 89

Basal cell carcinoma and squamous cell carcinoma are the most frequent types of cancer in the United States and represent 75 percent and 20 percent, respectively, of all nonmelanoma skin cancers. Since ultraviolet radiation is implicated in their development, photoprotection is fundamental in their prevention. Additional preventive measures include identifying high-risk individuals for early detection along with using agents, such as retinoids, that are effective in decreasing the risk of premalignant cells further developing into carcinomas. Newer agents achieving this goal include perillyl alcohol, T4 endonuclease 5, DL-alpha-tocopherol, and alpha-difluoromethylornithine. Procedural modalities are currently the standard of treatment, but recent evidence has consistently shown that newer (nonsurgical) therapies, such as interferon, imiquimod, retinoids, and 5-fluorouracil, can be used effectively either as monotherapies or as adjuvants to those surgical modalities for the treatment of superficial nonmelanoma skin cancers and premalignant lesions. These newer therapies have achieved significant reductions in morbidity and mortality. Procedural modalities that have been evolving into important tools for the treatment of actinic keratosis and nonmelanoma skin cancers include photodynamic therapy and lasers. Nonsurgical therapies currently proving to be effective in clinical trials include ingenol mebutate and cyclooxygenase-2 inhibitors. Agents that are showing promising results in early phases of clinical trials include betulinic acid; hedgehog signaling pathway inhibitors, such as cyclopamine and GDC-0449; alpha-melanocyte-stimulating hormone analogs, such as afamelanotide; epidermal growth factor receptor inhibitors, such as gefitinib and erlotinib; anti-epidermal growth factor receptor monoclonal antibodies, such as cetuximab and panitumumab; and the 5-fluorouracil prodrug capecitabine.
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PMID:Nonsurgical innovations in the treatment of nonmelanoma skin cancer. 2072 48


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