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)

The stability of transferrin receptor (TfR) mRNA is regulated by iron availability. When a human plasma-cytoma cell line (ARH-77) is treated with an iron source (hemin), the TfR mRNA is destabilized and a shorter TfR RNA appears. A similar phenomenon is also observed in mouse fibroblasts expressing a previously characterized iron-regulated human TfR mRNA (TRS-1). In contrast, mouse cells expressing a constitutively unstable human TfR mRNA (TRS-4) display the shorter RNA irrespective of iron treatment. These shorter RNAs found in both the hemin-treated ARH-77 cells and in the mouse fibroblasts are shown to be the result of a truncation within the 3' untranslated regions of the mRNAs. The truncated RNA is generated by an endonuclease, as most clearly evidenced by the detection of the matching 3' endonuclease product. The cleavage site of the human TfR mRNA in the mouse fibroblasts has been mapped to single nucleotide resolution to a single-stranded region near one of the iron-responsive elements contained in the 3' UTR. Site-directed mutagenesis demonstrates that the sequence surrounding the mapped endonuclease cleavage site is required for both iron-regulated mRNA turnover and generation of the truncated degradation intermediate. The TfR mRNA does not undergo poly(A) tail shortening prior to rapid degradation since the length of the poly(A) tail does not decrease during iron-induced destabilization. Moreover, the 3' endonuclease cleavage product is apparently polyadenylated to the same extent as the full-length mRNA.
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PMID:Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 3' UTR and does not involve poly(A) tail shortening. 790 15

Previously, a small region of the 3'-untranslated region (3' UTR) of Xlhbox2B mRNA was shown to be sufficient for sequence-specific endonucleolytic cleavage after injection into Xenopus oocytes. Here, we report an in vitro RNA degradation reaction that mimics the in vivo result accurately. The reaction also reveals that oocytes contain a sequence-specific RNA-binding factor that inhibits the endoribonuclease. These opposing activities may be regulated during Xenopus oogenesis. Partial purification shows that the endonuclease does not require translation or ribosomes and does not resemble previously described RNA processing complexes. We have isolated another Xenopus cDNA, Xoo1, that contains a long, repetitive destabilizing element similar to the one in Xlhbox2B. Based on a comparison of these natural destabilizing sequences and in vitro mutagenesis experiments, we find that a single destabilizing site is, at most, 19 bases in length and that the endonuclease and protective factor recognition sites may be overlapping subsets of this sequence. Finally, we show that Drosophila embryos contain similar activities, each of which can use Xenopus recognition sites. This level of conservation suggests an important biological function for this system of post-transcriptional regulation.
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PMID:Sequence-specific endonucleolytic cleavage and protection of mRNA in Xenopus and Drosophila. 833 37

While the potential importance of mRNA stability to the regulation of gene expression has been recognized, the structures and mechanisms involved in the determination of individual mRNA decay rates have just begun to be elucidated, particularly in mammalian systems and yeast. It is now well established that mRNA decay is not a default process, in which an array of nonspecific nucleases degrades indiscriminately based on target size or ribosome protection of the substrate. Rather, like transcription, RNA processing, and translation, mRNA decay is a precise process dependent on a variety of specific cis-acting sequences and trans-acting factors. Entry into the pathways of mRNA decay is triggered by at least three types of initiating event: poly(A) shortening, arrest of translation at a premature nonsense codon, and endonucleolytic cleavage. Steps subsequent to poly(A) shortening or premature translational termination converge in a pathway that progresses from removal of the 5' cap to exonucleolytic digestion of the body of the mRNA. mRNA fragments generated by endonucleolytic cleavage are most likely removed by exonucleolytic decay as well, but these events have not been characterized in detail. Nucleases and other factors (including mRNA sequence elements and autoregulatory proteins) required for the promotion or inhibition of these pathways have been identified by both biochemical and genetic methods and systematic attempts to understand their respective roles have begun. mRNA sequences whose presence or absence has marked effects on mRNA decay rates include the ubiquitous cap and poly(A) tail, sequences that comprise endonuclease cleavage sites, and sequences that promote poly(A) shortening. The latter are found in the 3'-UTR (untranslated region) and in coding regions. Evidence that poly(A) stimulates translation initiation, that some destabilization sequences must be translated in order to function, and that premature translation termination promotes rapid mRNA decay indicates a close linkage between the elements regulating mRNA decay and components of the protein synthesis apparatus. This linkage, and other data, leads us to propose a model for a functional mRNP. In this model, interactions between factors associated with opposite ends of an mRNA stimulate translation initiation and minimize the rate of entry into the pathways of mRNA decay. Events that initiate mRNA decay are postulated to be those that can disrupt this functional complex and create substrates for exonucleolytic digestion.
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PMID:Interrelationships of the pathways of mRNA decay and translation in eukaryotic cells. 881 Nov 93

Previous work from this laboratory [Dompenciel,R.E., Garnepudi,V.R. and Schoenberg,D.R. (1995)J. Biol. Chem.270, 6108-6118] described the purification and properties of an estrogen-regulated endonuclease isolated from Xenopus liver polysomes that is involved in the destabilization of albumin mRNA. The present study mapped cleavages made by this enzyme onto the secondary structure of the portion of albumin mRNA bearing the major cleavage sites. The predominant cleavages occur in the overlapping APyrUGA sequence AUUGACUGA present in a single-stranded loop region, and in AUUGA located within a bulged AU-rich stem. A structural mutation which converted the major loop cleavage site to a hairpin bearing one APyrUGA element eliminated cleavage at the intact site. This confirms that the polysomal RNase is specific for single-stranded RNA. Additional point mutations in the major loop characterized the nucleoside sequence requirements for cleavage. Finally, snake venom exonuclease was used to demonstrate the polysomal RNase generates products with a 3' hydroxyl. Binding of an estrogen-induced protein to a portion of the 3'UTR of vitellogenin mRNA may be involved in its stabilization by estrogen [Dodson,R.E. and Shapiro,D.J. (1994)Mol. Cell. Biol.14, 3130-3138]. The core binding site for this protein bears the sequence APyrUGA, suggesting that stabilization may be accomplished by occlusion of a cleavage site for the polysomal RNase.
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PMID:Cleavage properties of an estrogen-regulated polysomal ribonuclease involved in the destabilization of albumin mRNA. 901 22

The distribution between the different hepatitis C virus genotypes and subtypes has potentially important clinical and epidemiological implications. With this view a simple restriction fragment length polymorphism (RFLP) based assay was developed to identify the three major genotypes, 1, 2 and 3 and distinguish subtype 1a from 1b. This RFLP test uses a combination of three restriction endonuclease digestions, BstN1, BstU1 and Sau3a, respectively. Comparison with a 5'UTR based assay (LiPA), showed a 98% concordance with the RFLP based assay. In addition, good concordance is shown between these data and those obtained with a serological assay based on NS4 peptides.
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PMID:Development of a simple restriction fragment length polymorphism (RFLP) based assay for HCV genotyping and comparative analysis with genotyping and serotyping tests. 912 57

The 20S proteasome (prosome) is a highly organized multiprotein complex with approximate molecular weight of about 700 kDa. Whilst the role of the proteasome in the processing and turnover of cellular proteins is becoming clearer, its relationship with RNA remains still obscure. Here we focus on the nature and function of proteasome associated endonuclease activity. Thus the involvement of a proteasome alpha-type subunit in RNA-degradation, the catalytic requirements, the interaction of proteasomes with their RNA-substrate and the identification of a well defined cleavage site in the 3'UTR of short-lived cellular mRNAs will be described in detail. All data indicate that proteasomes associated endonuclease activity could be involved in post-transcriptional gene control at the level of translation.
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PMID:Proteasome (prosome) associated endonuclease activity. 922 91

Clonal rearrangements of the Ig heavy chain (IGH) locus consisting of either intrachromosomal (VDJ) rearrangements or interchromosomal translocations are a consistent feature of all B-cell malignancies and may be used both diagnostically and to monitor response to therapy. Many of these rearrangements are targeted to the IGHJ segments, but only some can be amplified with regular polymerase chain reaction (PCR) techniques. To permit PCR amplification of potentially all IGHJ rearrangements, we have devised a method incorporating self-ligation of restriction endonuclease-digested DNA fragments with long-distance PCR (long-distance, inverse PCR [LDI-PCR]). We show here, using only 4 nested oligonucleotide primers, the successful amplification and DNA sequencing of all IGHJ rearrangements up to 5.4 kb in length from a panel of 13 cases and cell lines of various types of B-cell malignancy. In all cases, both VDJ and DJ IGH rearrangements and translocation breakpoints were amplified. Six cases exhibited t(14;18)(q32;q21). All translocation breakpoints were cloned and sequenced. Three cases exhibited a rearrangement to the BCL2 major breakpoint region (MBR). However, 2 other cases exhibited rearrangements between the MBR and the minor cluster region (mcr). These 2 cases broke within 44 bp of each other, confirming the presence of an additional 3' BCL2 breakpoint cluster region. The final case fell immediately 3' of the 3' UTR of the BCL2 gene adjacent to an Alu repeat. No other BCL2 breakpoints within this region have been reported. Four cases exhibited t(11;14)(q13;q32). All 3 cases with translocations targeted to the IGHJ segments were successfully amplified and sequenced, including 1 case in which the BCL1 translocation could not be detected by DNA blot using the currently available probes. All three translocation breakpointsfell outside the BCL1 major translocation cluster between 20 and 40 kb telomeric and showed no clustering. Two of the three fell within or adjacent to Alu repeat regions. LDI-PCR is a simple and robust technique that allows PCR amplification of nearly all IGHJ rearrangements.
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PMID:Rapid molecular cloning of rearrangements of the IGHJ locus using long-distance inverse polymerase chain reaction. 931 Apr 98

In the silkworm, Bombyx mori, a non-long terminal repeat (non-LTR) retrotransposon, BMC1, is considered to be a LINE (long interspersed nuclear element)-like element. So far, a BMC1 containing two intact open reading frames (ORFs) has not been found. However, we discovered a complete full-length BMC1 on the W chromosome. This BMC1 is 5091 bp and contains a 5' untranslated region (5'-UTR), two intact ORFs, and 3'-UTR which terminates in a poly(A) tail. ORF1 encodes a putative nucleic acid-binding protein, while ORF2 encodes a protein containing an endonuclease domain and a reverse transcriptase domain.
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PMID:A complete full-length non-LTR retrotransposon, BMC1, on the W chromosome of the silkworm, Bombyx mori. 1033 66

In looking for genes that escape X chromosome inactivation, we scanned the methylation status of genomic DNA from XX, X0, and XY mice using the method of restriction landmark genomic scanning using methylation-sensitive endonuclease. We detected and cloned a candidate locus and identified the Orf1 gene. Orf1 has sequence similarities to the B2 repetitive element and human CXORF4 (formerly called EXLM1), which escapes X inactivation. The B2 element spans the 3' terminus of the ORF and the 3' UTR of Orf1. The Orf1 gene encompasses 18.5 kb of genomic DNA including 11 exons and 10 introns. Taking advantage of genomic polymorphisms present between MSM and C3H/He, we showed that murine Orf1 is mapped to the proximal region of the X chromosome. Despite the unmethylation of the NotI site, Orf1 is subject to X inactivation.
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PMID:Detection and cloning of an X-linked locus associated with a NotI site that is not methylated on mouse inactivated X chromosome by the RLGS-M method. 1051 84

Patients with chronic renal failure develop secondary hyperparathyroidism with increased synthesis and secretion of parathyroid hormone (PTH) resulting in severe skeletal complications. In rats with secondary hyperparathyroidism due to 5/6 nephrectomy, there are increased PTH mRNA levels, and this mechanism was studied. Parathyroid glands were microdissected from control and 5/6 nephrectomy rats and analyzed for PTH mRNA and control genes, and the nuclei were used for nuclear run-on experiments. The cytosolic proteins of the parathyroids were used to study PTH mRNA protein binding by ultraviolet cross-linking and the degradation of the PTH transcript in vitro. Nuclear run-ons showed that the increase in PTH mRNA levels was posttranscriptional. Protein binding to the PTH mRNA 3'-UTR determines PTH mRNA stability and levels. Parathyroid proteins from uremic rats bound PTH mRNA similar to control rats by ultraviolet cross-linking. To determine the effect of uremia on PTH mRNA stability, an in vitro RNA degradation assay was performed with parathyroid proteins from uremic rats. When parathyroid proteins from control rats were incubated with PTH mRNA, there was transcript degradation already at 30 min, reaching 50% at 60 min and 90% at 180 min. With uremic parathyroid proteins, the PTH mRNA was not degraded at all at 120 min and was moderately decreased at 180 min. This decrease in degradation by uremic parathyroid proteins suggests a decrease in parathyroid cytosolic endonuclease activity in uremia resulting in a more stable PTH transcript. The increased PTH mRNA levels would translate into increased PTH synthesis and serum PTH levels, which would lead to metabolic bone disease in many patients with chronic renal failure.
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PMID:Mechanism of increased parathyroid hormone mRNA in experimental uremia: roles of protein RNA binding and RNA degradation. 1058 95


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