Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The overall aim of our group's work is to investigate the molecular mechanisms regulating erythroid cell-specific gene expression during erythroid cell differentiation. We have been successful in cloning two non-globin genes of interest: the first encodes the rabbit red cell-specific lipoxygenase (LOX), which has a role in degrading mitochondrial lipids during maturation of the reticulocyte to the erythrocyte; and the second, mouse glutathione peroxidase (GSHPX), an important seleno-enzyme responsible for protection against peroxide-damage. Characterization of the GSHPX gene revealed that the seleno-cysteine residue in the active site of the enzyme is encoded by UGA, which usually functions as a translation-termination codon. This novel finding has important implications regarding the role of mRNA sequence context effects in codon recognition. In contrast with the beta-globin locus, very little is known about the mechanisms responsible for the erythroid-specific expression of the alpha-globin genes. By a combination of functional transfection assays and studies of the interactions of nuclear sequence-specific DNA-binding proteins with promoter sequences in vitro, we have recently defined two regions upstream of the mouse alpha-globin gene involved in its erythroid-specific expression: one contains a sequence motif (GATAAG) that binds to a species-conserved and erythroid-specific factor both in vitro and in vivo. Interestingly, GATAAG motifs binding the same factor are found also in the mouse and chicken adult beta-globin gene promoters, the erythroid-specific promoter of the haem pathway enzyme, porphobilinogen (PBG) deaminase and the chicken beta-globin 3' enhancer. We are now commencing purification of this erythroid-specific GATAAG-binding factor, investigating in more detail how it functions in relation to other globin gene control regions and determining whether GATAAG-like regions have a functional role in the erythroid-specific expression of other genes. We have begun to investigate the regulation of the GSHPX and red cell LOX genes. The presence of tissue-specific 3' DNAse I-hypersensitive sites (DHSS) suggests that different 3' flanking regions of the GSHPX gene may be important in its regulation in the various cell types in which it is highly expressed, i.e. erythroid cells, liver and kidney.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:cis and trans control of erythroid cell-specific gene expression during erythropoiesis. 315 55

C-->U RNA editing of neurofibromatosis 1 (NF1) mRNA changes an arginine (CGA) to a UGA translational stop codon, predicted to result in translational termination of the edited mRNA. Previous studies demonstrated varying degrees of C-->U RNA editing in peripheral nerve-sheath tumor samples (PNSTs) from patients with NF1, but the basis for this heterogeneity was unexplained. In addition, the role, if any, of apobec-1, the catalytic deaminase that mediates C-->U editing of mammalian apolipoprotein B (apoB) RNA, was unresolved. We have examined these questions in PNSTs from patients with NF1 and demonstrate that a subset (8/34) manifest C-->U editing of RNA. Two distinguishing characteristics were found in the PNSTs that demonstrated editing of NF1 RNA. First, these tumors express apobec-1 mRNA, the first demonstration, in humans, of its expression beyond the luminal gastrointestinal tract. Second, PNSTs with C-->U editing of RNA manifest increased proportions of an alternatively spliced exon, 23A, downstream of the edited base. C-->U editing of RNA in these PNSTs was observed preferentially in transcripts containing exon 23A. These findings were complemented by in vitro studies using synthetic RNA templates incubated in the presence of recombinant apobec-1, which again confirmed preferential editing of transcripts containing exon 23A. Finally, adenovirus-mediated transfection of HepG2 cells revealed induction of editing of apoB RNA, along with preferential editing of NF1 transcripts containing exon 23A. Taken together, the data support the hypothesis that C-->U RNA editing of the NF1 transcript occurs both in a subset of PNSTs and in an alternatively spliced form containing a downstream exon, presumably an optimal configuration for enzymatic deamination by apobec-1.
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PMID:C-->U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme. 1172 99

Cystic fibrosis (CF) is caused by mutations in the gene encoding the transmembrane conductance regulator (CFTR) protein. Some CF patients are compound heterozygous or homozygous for nonsense mutations in the CFTR gene. This implies the presence in the transcript of premature termination codons (PTCs) responsible for a truncated CFTR protein and a more severe form of the disease. Aminoglycoside and PTC124 derivatives have been used for the read-through of PTCs to restore the full-length CFTR protein. However, in a precision medicine framework, the CRISPR/dCas13b-based molecular tool "REPAIRv2" (RNA Editing for Programmable A to I Replacement, version 2) could be a good alternative to restore the full-length CFTR protein. This RNA editing approach is based on the targeting of the deaminase domain of the hADAR2 enzyme fused to the dCas13b protein to a specific adenosine to be edited to inosine in the mutant mRNA. Targeting specificity is allowed by a guide RNA (gRNA) complementarily to the target region and recognized by the dCas13b protein. Here, we used the REPAIRv2 platform to edit the UGA PTC to UGG in different cell types, namely IB3-1 cells, HeLa, and FRT cells engineered to express H2BGFPopal and CFTRW1282X, respectively.
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PMID:Investigating REPAIRv2 as a Tool to Edit CFTR mRNA with Premature Stop Codons. 3264 Jun 50