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)

The lysosomal enzyme, beta-hexosaminidase, is composed of two chains, alpha and beta. In Tay-Sachs disease, mutations in the gene encoding the alpha-chain produce a beta-hexosaminidase deficiency that results in the storage of its natural substrate, GM2 ganglioside. To obtain the background information for the eventual identification of the mutational errors in Tay-Sachs disease and to determine possible relationships between protein and gene structure, we have characterized the intron-exon organization of the human beta-hexosaminidase alpha-chain gene. Several overlapping clones were isolated from human genomic libraries constructed in cosmid and bacteriophage vectors. The cloned genomic DNA was analyzed by restriction endonuclease mapping, Southern blotting, and DNA sequencing. It was determined that the alpha-chain gene is approximately 35 kilobases long and is split into 14 exons. Sequences which resemble the "TATA" and "CAAT" transcriptional regulatory motifs are present at the 5' end of the gene. Differential transcription or processing of the most 3' exon of the gene results in two alpha-chain mRNAs with different 3'-untranslated regions. The first exon of the gene encodes the amino-terminal portion of the alpha-chain which is removed during the proteolytic maturation of the enzyme, raising the possibility that this segment may exist as a functional domain.
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PMID:Organization of the gene encoding the human beta-hexosaminidase alpha-chain. 295 41

Monosialogangliosides, normal components of cell membranes, regulate cell development and differentiation in several organs. Our previous observation of dramatic premature thymic involution in cats with feline GM1 gangliosidosis, whose thymocytes have abnormally high cell surface gangliosides, suggested that excess GM1 ganglioside (GM1) could modulate thymocyte apoptosis in this disease (Cox et al., "Thymic Alterations in Feline GM1 Gangliosidosis," submitted). In these studies, we added exogenous GM1 to murine primary thymocyte cultures and demonstrated enhanced apoptosis in treated cells by DNA fragmentation, apoptotic body, and electrophoretic analyses. GM1-enhanced apoptosis was blocked by common apoptotic pathway inhibitors including aurintricarboxylic acid (inhibitor of endonuclease activity), actinomycin D (inhibitor of RNA transcription), and cycloheximide (inhibitor of protein synthesis). GM1 treatment primarily affected the immature CD4+ CD8+ subset, as shown by flow cytometric evaluation of fetal thymic organ culture and primary thymocyte cultures. Apoptosis also could be induced by GM2, GM3, and GT1b, whereas asialo-GM1 failed to do so, suggesting that the sialic acid moiety may play an important role in the induction of thymocyte apoptosis.
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PMID:Gangliosides enhance apoptosis of thymocytes. 960 92

Complex ganglioside expression is highly deregulated in several tumors which is further dependent on specific ganglioside synthase genes. Here, we designed and constructed a pair of highly specific transcription-activator like effector endonuclease (TALENs) to disrupt a particular genomic locus of mouse GM2-synthase, a region conserved in coding sequence of all four transcript variants of mouse GM2-synthase. Our designed TALENs effectively work in different mouse cell lines and TALEN induced mutation rate is over 45%. Clonal selection strategy is undertaken to generate stable GM2-synthase knockout cell line. We have also demonstrated non-homologous end joining (NHEJ) mediated integration of neomycin cassette into the TALEN targeted GM2-synthase locus. Functionally, clonally selected GM2-synthase knockout clones show reduced anchorage-independent growth (AIG), reduction in tumor growth and higher cellular adhesion as compared to wild type Renca-v cells. Insight into the mechanism shows that, reduced AIG is due to loss in anoikis resistance, as both knockout clones show increased sensitivity to detachment induced apoptosis. Therefore, TALEN mediated precise genome editing at GM2-synthase locus not only helps us in understanding the function of GM2-synthase gene and complex gangliosides in tumorigenicity but also holds tremendous potential to use TALENs in translational cancer research and therapeutics.
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PMID:TALEN mediated targeted editing of GM2/GD2-synthase gene modulates anchorage independent growth by reducing anoikis resistance in mouse tumor cells. 2576 67