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)

A comparative study of several parameters of the cell nuclei of hybridoma MLC-1c and its parent cells--myeloma X-63.Ag8.653 and spleen lymphocytes of Balb/c mice, has been carried out. The results of cytogenetic studies suggest that although the hybridoma and myeloma cell lines used in this study are rather stable, they contain some proportion of the altered chromosomal material. Two-dimensional electrophoresis performed according to O'Farrell revealed that the similarity between the relative presentation and reciprocal location of the nuclear proteins expressed by the myeloma and the hybridoma was greater than that between these cell lines and lymphocytes. Probing of the chromatin structure by micrococcal nuclease showed no significant differences in the degree of nuclease resistance of chromatin between myeloma, hybridoma and lymphoid cells. A comparative study of the Ca/Mg-dependent endonuclease activity of the nuclei in situ and in nuclear extracts demonstrated that whereas its content in lymphocytes was rather high, in myeloma and hybridoma it was practically absent. At the same time, cell nucleus extracts of the myeloma and the hybridoma contained high amounts of DNA-binding proteins which were undetectable in mouse spleen lymphocytes.
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PMID:[Comparative characteristics of some parameters of the cell nucleus in the series myeloma-hybridoma-lymphocyte]. 848 24

The Philadelphia (Ph) translocation [t(9;22)(q34;q11)] is the most common genetic abnormality in human leukemia; a transposition of the ABL gene to the major-breakpoint cluster region (M-BCR) is associated with the pathogenesis in Ph+ chronic myelogenous leukemia (Ph+ CML) and in some cases of Ph+ acute leukemia (Ph+ AL). Our current understanding of the methylation of human genomes allows us to consider the association between the epigenetic phenomenon and the control of differentiation and proliferation in mammalian cells. In order to determine whether the methylation status of the M-BCR is associated with breakpoint-localization in this region and with the lineage of hematopoietic cells, we have examined 28 patients with Ph+ leukemias, including nine with Ph+ AL, six patients with acute myeloblastic leukemia without Ph (Ph- AML), and five patients with Ph- acute lymphoblastic leukemia (Ph- ALL); using the restriction endonuclease isochizomers, MspI and HpaII. In CML patients in the chronic phase, the hypomethylated status within the normal M-BCR allele is heterogeneous. In contrast, patients with Ph+ CML in the lymphoid blast crisis phase exhibited a 2.5/2.7 kb band with a complete disappearance of the germline M-BCR fragment (type L). This pattern is consistently noted in Ph- ALL cells, and the pattern is quite different from that found in myeloid blast crisis or Ph- AML (type M). In patients with M-BCR-nonrearranged Ph+ ALL, it is suggested that the M-BCR methylation patterns are cell-lineage specific but some Ph+ ALL cells had a hypomethylation pattern that was identical to that observed in Ph- AML, suggesting a distinction of genetic diversity of leukemia cells with the Ph chromosome, especially Ph+ AL.
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PMID:The methylation status of the major breakpoint cluster region in human leukemia cells, including Philadelphia chromosome-positive cells, is linked to the lineage of hematopoietic cells. 850 75

The beta chain of human chorionic gonadotropin (hCG) hormone is produced by fetal cells, gonadal cell tumors and several types of non-gonadal carcinoma. hCG is composed of an alpha and a beta chain, the latter of which can be used to distinguish the molecule from other related gonadotropin hormones. Detection of beta-hCG mRNA transcripts can be potentially useful as a marker to identify tumor cells. We devised a highly specific and sensitive assay to detect the atavistic expression of beta-hCG in cutaneous melanoma by RT-PCR. Twenty-four melanoma cell lines and 43 melanoma biopsies were evaluated for beta-hCG mRNA expression. An RT-PCR assay was developed to specifically distinguish beta-hCG poly-A mRNA from other related gonadotropin beta chains. This was performed by endonuclease digestion of a unique Sty 1 site in the beta chain, followed by Southern blot analysis with a beta-hCG cDNA probe. Of the 24 melanoma cell lines analyzed, 18 expressed beta-hCG mRNA. Analysis of melanoma biopsy specimens revealed beta-hCG mRNA expression in 17/25 melanoma-positive TDLN, and in only 5/15 non-lymphoid melanoma metastases. Beta-hCG mRNA expression had a 53% correlation to tyrosinase mRNA, a predominant melanoma marker. Beta-hCG mRNA was not detected in normal donor PBL and normal lymph nodes. Detection of beta-hCG mRNA expression may be a useful molecular marker to define a subset of malignant melanoma.
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PMID:Detection of beta-human chorionic gonadotropin mRNA as a marker for cutaneous malignant melanoma. 862 Dec 27

B lymphocytes can alter selectively their immunoglobulin (Ig) isotype expressed by deletional rearrangement of the first active immunoglobulin heavy-chain (IgH) constant region (C mu) gene with one of six other constant region genes. Recombination breakpoints occur within highly repetitive "switch" (S) regions located upstream of each IgH constant region gene except C delta. Analysis of rearranged switch DNA junctions has not detected a consensus sequence, although the predominance of two pentamer motifs (TGGGG and TGAGC) at or near these breakpoints and throughout all murine S region sequences has led to their advocacy as the S recombination signals. In this paper, we describe the characterization and partial purification of a lymphoid-specific endo-nuclease activity which cleaves preferentially murine S region DNA. Enzyme activity selectively produced single- and double-stranded breaks at TGAGC and TGGG motifs within murine S mu and S alpha DNA. Rare cryptic cleavage sites were detected also within non-switch sequences, although cleavage intensities at these sites were reduced greatly, relative to consensus S region cleavages. Analogous activity was found in murine tissue extracts, although among the tissues assayed only spleen and thymus contained detectable activity. Subsequent biochemical characterization of this activity demonstrated that the responsible enzyme (Endo-SR) represented a previously unreported tissue-specific mammalian endonuclease. Endo-SR-specific activity could be enhanced by addition of Mg2+ or Ca2+ and inhibited by addition of Zn2+. Maximal specific activity was detected at pH 5.5 and sharply declined within +/- 0.5 pH units. In view of this enzyme's sequence- and tissue-specificity, we propose that Endo-SR is a strong candidate for an endonuclease activity associated with the switch recombination process.
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PMID:Characterization of an endonuclease activity which preferentially cleaves the G-rich immunoglobulin switch repeat sequences. 864 37

Anucleate cells can be induced to undergo programmed cell death (PCD), indicating the existence of a cytoplasmic PCD pathway that functions independently from the nucleus. Cytoplasmic structures including mitochondria have been shown to participate in the control of apoptotic nuclear disintegration. Before cells exhibit common signs of nuclear apoptosis (chromatin condensation and endonuclease-mediated DNA fragmentation), they undergo a reduction of the mitochondrial transmembrane potential (delta psi m) that may be due to the opening of mitochondrial permeability transition (PT) pores. Here, we present direct evidence indicating that mitochondrial PT constitutes a critical early event of the apoptotic process. In a cell-free system combining purified mitochondria and nuclei, mitochondria undergoing PT suffice to induce chromatin condensation and DNA fragmentation. Induction of PT by pharmacological agents augments the apoptosis-inducing potential of mitochondria. In contrast, prevention of PT by pharmacological agents impedes nuclear apoptosis, both in vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing apoptosis, but not those from normal cells, induce disintegration of isolated Hela nuclei. A specific ligand of the mitochondrial adenine nucleotide translocator (ANT), bongkreik acid, inhibits PT and reduces apoptosis induction by mitochondria in a cell-free system. Moreover, it inhibits the induction of apoptosis in intact cells. Several pieces of evidence suggest that the proto-oncogene product Bcl-2 inhibits apoptosis by preventing mitochondrial PT. First, to inhibit nuclear apoptosis, Bcl-2 must be localized in mitochondrial but not nuclear membranes. Second, transfection-enforced hyperexpression of Bcl-2 directly abolishes the induction of mitochondrial PT in response to a protonophore, a pro-oxidant, as well as to the ANT ligand atractyloside, correlating with its apoptosis-inhibitory effect. In conclusion, mitochondrial PT appears to be a critical step of the apoptotic cascade.
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PMID:Mitochondrial control of nuclear apoptosis. 866 86

Mature B lymphocytes are able to specifically alter their Ig isotype expression in response to extracellular stimuli via a highly regulated, deletional recombination process called isotype switch recombination. Switch recombination breakpoints predominantly map to large (1-10 kb), G-rich and highly repetitive switch regions that are located directly upstream of immunoglobulin heavy-chain constant region genes. Switch region repeat structures vary considerably both within and between species, but all switch regions contain disproportionate numbers of two pentamer motifs, TGGGN and TGAGC, that are found at or directly adjacent to most analysed switch junctions. We have recently identified an endonuclease activity, Endo SR, that preferentially cleaves TGGGN and TGAGC switch motifs. We have purified the bovine endonuclease activity to homogeneity and have identified a protein with a molecular weight of approximately 32,000 that directly correlates with enzyme activity. As discussed in this report, we have found that murine and bovine Endo-SR are preferentially enriched in lymphoid tissue nuclear extracts and that both enzymes demonstrate highly similar physical and biochemical characteristics. However, each enzyme demonstrates related but distinctive specificities for consensus and degenerate TGGGN and TGAGC switch pentamer motifs.
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PMID:Purification and characterization of the immunoglobulin switch sequence-specific endonuclease (Endo-SR) from bovine spleen. 922 63

In mammalian cells, single-base lesions, such as uracil and abasic sites, appear to be repaired by at least two base excision repair (BER) subpathways: "single-nucleotide BER" requiring DNA synthesis of just one nucleotide and "long patch BER" requiring multi-nucleotide DNA synthesis. In single-nucleotide BER, DNA polymerase beta (beta-pol) accounts for both gap filling DNA synthesis and removal of the 5'-deoxyribose phosphate (dRP) of the abasic site, whereas the involvement of various DNA polymerases in long patch BER is less well understood. Recently, we found that beta-pol plays a role in mammalian cell extract-mediated long patch BER, in that formation of a key excision product, 5'-dRP-trinucleotide (5'-dRP-N(3)), is dependent upon beta-pol (Dianov, G. L., Prasad, R., Wilson, S. H., and Bohr, V.A. (1999) J. Biol. Chem. 274, 13741-13743). The structure-specific endonuclease flap endonuclease 1 (FEN1) has also been suggested to be involved in long patch BER excision. Here, we demonstrate by immunodepletion experiments that 5'-dRP-N(3) excision in long patch BER of uracil-DNA in a human lymphoid cell extract is, indeed, dependent upon FEN1. Next, we reconstituted the excision step of long patch BER using purified human proteins and an oligonucleotide substrate with 5'-dRP at the margin of a one-nucleotide gap. Formation of the excision product 5'-dRP-N(3) was dependent upon both strand displacement DNA synthesis by beta-pol and FEN1 excision. FEN1 stimulated strand displacement DNA synthesis of beta-pol. FEN1 acting either alone, or without DNA synthesis by beta-pol, produced a two-nucleotide excision product, 5'-dRP-N(1), but not 5'-dRP-N(3). These results demonstrate that human FEN1 and beta-pol can cooperate in long patch BER excision and specify the predominant excision product seen with a cell extract.
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PMID:FEN1 stimulation of DNA polymerase beta mediates an excision step in mammalian long patch base excision repair. 1066 Jun 19

Defects in the nonhomologous end-joining (NHEJ) pathway of double-stranded DNA break repair severely impair V(D)J joining and selectively predispose mice to the development of lymphoid neoplasia. This connection was first noted in mice with the severe combined immune deficient (SCID) mutation in the DNA-dependent protein kinase (DNA-PK). SCID mice spontaneously develop thymic lymphoma with low incidence and long latency. However, we and others showed that low-dose irradiation of SCID mice dramatically increases the frequency and decreases the latency of thymic lymphomagenesis, but irradiation does not promote the development of other tumors. We have used this model to explore the mechanistic basis by which defects in NHEJ confer selective and profound susceptibility to lymphoid oncogenesis. Here, we show that radiation quantitatively and qualitatively improves V(D)J joining in SCID cells, in the absence of T-cell receptor-mediated cellular selection. Furthermore, we show that the lymphocyte-specific endonuclease encoded by the recombinase-activating genes (RAG-1 and RAG-2) is required for radiation-induced thymic lymphomagenesis in SCID mice. Collectively, these data suggest that irradiation induces a DNA-PK-independent NHEJ pathway that facilitates V(D)J joining, but also promotes oncogenic misjoining of RAG-1/2-induced breaks in SCID T-cell precursors.
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PMID:Irradiation promotes V(D)J joining and RAG-dependent neoplastic transformation in SCID T-cell precursors. 1113 29

A putative oncogene bcl-3 was originally identified and cloned at the breakpoint in the recurring chromosome translocation t(14;19) found in some cases of B cell chronic lymphocytic leukemia. Studies of bcl-3-deficient mice demonstrated a critical role for bcl-3 in the development of a normal immune response and the formation of germinal centers in secondary lymphoid organs. However, the molecular mechanism that underlies B cell leukemogenesis and the knockout mouse phenotype remains unclear. Here we have identified and characterized BCL-3-binding protein (B3BP) as a protein interacting specifically with the bcl-3 gene product (BCL-3) by a yeast two-hybrid screen. We found that B3BP associates with not only BCL-3 but also p300/CBP histone acetyltransferases. The N-terminal region of B3BP that contains the ATP-binding site is important for the interaction with BCL-3 and p300/CBP. Homology searches indicate that the ATP-binding region of B3BP, which contains a typical Walker-type ATP-binding P-loop, most resembles that of 2',3'-cyclic nucleotide 3'-phosphodiesterase of mammals and polynucleotide kinase of T4 bacteriophage. In fact B3BP shows intrinsic ATP binding and hydrolyzing activity. Furthermore, we demonstrated that B3BP is a 5'-polynucleotide kinase. We also found a small MutS-related domain, which is thought to be involved in the DNA repair or recombination reaction, in the C-terminal region of B3BP, and it shows nicking endonuclease activity. These observations might help to gain new insights into the function of BCL-3 and p300/CBP, especially the coupling of transcription with repair or recombination.
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PMID:Identification and characterization of BCL-3-binding protein: implications for transcription and DNA repair or recombination. 1273 Jan 95

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


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