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:3.1.31.1 (micrococcal nuclease)
2,818 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The affinity of 2 methylating agents, N-methyl-N-nitrosourea (MNU), a potent carcinogen, and dimethyl sulfate (DMS), a very weak or non-carcinogen, for specific structural or functional regions of DNA has been studied in an in vitro system using rat liver nuclei. The release of alkylated nucleotides from nuclei following limited nuclease digestion was measured. Under restrictive conditions, pancreatic DNase I preferentially digests DNA sequences active in RNA transcription while micrococcal nuclease digests spacer DNA between nucleosome cores. Nucleotides methylated by methylnitrosourea were preferentially released early during the digestions, suggesting a localization in both actively transcribing regions and spacer DNA. DMS alkylation, on the other hand, showed a random distribution in chromosomal DNA as measured by micrococcal nuclease and only limited accumulation in transcribing DNA.
Cancer Lett 1981 May
PMID:Methylation of chromosomal DNA by two alkylating agents differing in carcinogenic potential. 730 35

The activated c-Ha-rasVal12 oncogene is often involved in the genesis of human malignancies. We show here that in c-Ha-rasVal12 oncogene-transformed mouse NIH 3T3 fibroblasts the copy number and expression level of the mutant ras oncogene correlates with the degree of chromatin decondensation, as assessed by micrococcal nuclease (MNase) and DNase I digestion. MNase and DNase I analyses further revealed that the nucleosomal repeat lengths were different in the normal and ras oncogene-transformed cells, 162.3 bp and 178.1 bp, respectively. These chromatin changes were accompanied by alterations in the content of histone H1 zero. Furthermore, using DNase I as a probe, we discovered that serum stimulation of normal and transformed cells, synchronized by serum starvation, induces rapid reversible changes in the structure of bulk chromatin that may be linked to transcriptional activation. Our data thus indicate that cell transformation by ras is associated with specific changes in chromatin structure that make it more vulnerable, and prone to additional mutations characteristic of cancer development in vivo.
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PMID:Cell transformation by c-Ha-rasVal12 oncogene is accompanied by a decrease in histone H1 zero and an increase in nucleosomal repeat length. 772 50

Poly(ADP-ribose) polymerase (PADPRP) catalyzes the transfer of multiple ADP-ribose units from NAD to nuclear histone and nonhistone proteins, a reaction that appears to be important in the rejoining of DNA strand breaks during DNA repair and replication. We previously established and characterized a HeLa cell line that was stably transfected with a recombinant expression plasmid containing the mouse mammary tumor virus promoter upstream of a construct encoding PADPRP antisense RNA. We now show that after depletion of PADPRP mRNA as a result of antisense RNA expression, normal PADPRP mRNA concentrations are restored between 8 and 16 h after removal of dexamethasone (which activates the mouse mammary tumor virus promoter). By depleting antisense cells of PADPRP, we demonstrated the contribution of this enzyme to various aspects of nuclear structure and function: (a) amplification of a selectable gene encoding three early enzymes in the pyrimidine biosynthetic pathway was greatly increased in cells depleted of PADPRP; (b) chromatin structure was significantly altered in PADPRP-depleted cells, as indicated by reduced initiation and elongation of poly(ADP-ribose) chains attached to various nuclear protein acceptors, lower levels of poly(ADP-ribosyl)ation of histone H1, and an increased susceptibility of DNA to micrococcal nuclease digestion; and (c) the survival of PADPRP-depleted antisense cells exposed to the DNA alkylating and carcinogenic agent methyl methanesulfonate or nitrogen mustard was significantly reduced relative to that of control cells.
Cancer Res 1994 Sep 01
PMID:Depletion of nuclear poly(ADP-ribose) polymerase by antisense RNA expression: influences on genomic stability, chromatin organization, and carcinogen cytotoxicity. 806 55

Apoptosis is the predominant form of cell death observed in a variety of physiological and pathological conditions such as cancer involution, insect metamorphosis, the development of the immune and nervous systems, and embryogenesis. The typical nuclear changes taking place in apoptotic cells include extensive condensation of chromatin and internucleosomal DNA fragmentation into units of 200 base pairs. However, the mechanisms responsible for both chromatin condensation and DNA fragmentation have yet to be elucidated. In this study, micrococcal nuclease and the divalent cations, Ca2+ and Mg2+, were applied to isolated nuclei in an attempt to reconstitute in vitro the digestion of genomic DNA associated with apoptosis. Micrococcal nuclease was found to induce a typical pattern of DNA fragmentation, but did not give rise to chromatin condensation, whereas Ca2+/Mg2+ induced both chromatin condensation and DNA fragmentation in isolated mouse liver nuclei. When the endonuclease inhibitor ZnCl2 was used, the DNA fragmentation induced by Ca2+/Mg2+ in nuclei could be completely inhibited, but chromatin condensation still occurred. For comparison, intact liver cells were treated with valinomycin, a potassium ionophore, which gave rise to an atypical cell death, with chromatin condensation appearing without DNA fragmentation. Our results suggest that endonuclease activation in apoptosis is neither necessary nor sufficient to induce chromatin condensation, and that DNA fragmentation and chromatin condensation may be triggered through separate pathways during apoptosis.
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PMID:Separate metabolic pathways leading to DNA fragmentation and apoptotic chromatin condensation. 829 67

Studies were performed to determine whether novobiocin can be used to enhance cisplatin (CDDP) cytotoxicity in a human small-cell lung carcinoma cell line, GLC4/CDDP, resistant to CDDP. Continuous incubation with novobiocin enhanced the cytotoxicity of CDDP treatment 1.9-fold in the parental cell line GLC4, but had no effect on its cytotoxicity in the resistant cell line GLC4/CDDP. Short incubation with novobiocin enhanced the cytotoxicity of CDDP treatment in GLC4 and GLC4/CDDP by a factor of 4.1 and 2.8, respectively. Using the latter schedule, the amount of CDDP-induced DNA interstrand cross-links (DNA ISC) at 4 hr as well as at 24 hr after novobiocin and CDDP treatment was higher in GLC4 than in GLC4/CDDP. In this case, the amount of DNA ISC had increased 1.6-fold in GLC4 and 1.3-fold in GLC4/CDDP at 4 hr, and 2.7-fold and 1.4-fold, respectively, in these cell lines at 24 hr after treatment compared to CDDP treatment alone. Our results suggest an effect of novobiocin on the formation of DNA ISC. The decreased efficacy of novobiocin, an inhibitor of DNA topoisomerase (Topo) II catalytic activity, in GLC4/CDDP may be due to the increased Topo II activity previously found in the resistant cells. In the present study, we showed that increased Topo II activity was not due to changes in amounts of Topo II in nuclei or nuclear extracts of GLC4/CDDP. Further analysis of the chromatin, that includes Topo II, showed that the chromatin in nuclei of GLC4/CDDP was more sensitive to micrococcal nuclease digestion than GLC4. In addition, the amount of a 56-kDa protein was increased 2-fold in nuclei and nuclear matrices from GLC4/CDDP. The reduced efficacy of novobiocin to increase the CDDP cytotoxicity as well as the formation of DNA ISC in GLC4/CDDP compared to GLC4 may be due to changes in the chromatin structure of the resistant cells.
Int J Cancer 1993 Jan 02
PMID:Effect of novobiocin on cisplatin cytotoxicity and DNA interstrand cross-link formation in a cisplatin-resistant, small-cell lung carcinoma cell line. 838 54

Telomerase is a ribonucleoprotein that catalyzes telomere elongation through the addition of TTAGGG repeats in humans. Activation of telomerase is often associated with immortalization of human cells and cancer. To dissect the human telomerase enzyme mechanism, we developed a functional in vitro reconstitution assay. After removal of the essential 445 nucleotide human telomerase RNA (hTR) by micrococcal nuclease digestion of partially purified human telomerase, the addition of in vitro transcribed hTR reconstituted telomerase activity. The activity was dependent upon and specific to hTR. Using this assay, truncations at the 5' and 3' ends of hTR identified a functional region of hTR, similar in size to the full-length telomerase RNAs from ciliates. This region is located between positions 1-203. Furthermore, we found that residues 1-44, 5' to the template region (residues 46-56) are not essential for activity, indicating a minimal functional region is located between residues 44-203. Mutagenesis of full-length hTR between residues 170-179, 180-189 or 190-199 almost completely abolished the ability of the hTR to function in the reconstitution of telomerase activity, suggesting that sequences or structures within this 30 nucleotide region are required for activity, perhaps by binding telomerase protein components.
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PMID:Reconstitution of human telomerase activity and identification of a minimal functional region of the human telomerase RNA. 891 70

Disorder in sister chromatid separation can lead to genome instability and cancer. A temperature-sensitive S. pombe mis6-302 frequently loses a minichromosome at 26 degrees C and abolishes equal segregation of regular chromosomes at 36 degrees C. The mis6+ gene is essential for viability, and its deletion results in missegregation identical to mis6-302. Mis6 acts before or at the onset of S phase, and mitotic missegregation defects are produced only after the passage of G1/S at 36 degrees C. Mis6 locates at the centromeres throughout the cell cycle. In the mutant, positioning of the centromeres becomes abnormal, and specialized chromatin in the inner centromeres, which give the smear micrococcal nuclease pattern in wild type, is disrupted. The ability to establish correct biorientation of sister centromeres in metaphase cells requires the Mis6-containing chromatin and originates during the passage of G1/S.
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PMID:Mis6, a fission yeast inner centromere protein, acts during G1/S and forms specialized chromatin required for equal segregation. 923 Mar 9

Zinc (Zn) is a trace element in human cells and regarded as an essential nutrient with established deficiency states affecting multiple organs in the body. However, it has been reported that Zn uptake is associated with some serious harmful effects, such as inhibition of DNA synthesis and enhanced toxicity from reactive oxygen species. We have previously shown that in vivo administration of Zn2+ in C57/6J mice induces weight loss and massive hair loss where the normal course hair becomes replaced by fine vello hair, simulating the side effects from cancer chemotherapy where oxidative free radical damage is implicated in association with DNA fragmentation and programmed cell death (PCD). Here, in vitro flow cytometric studies on human Chang liver showed Zn2+ causing cell condensation with DNA fragmentation that occurred in a dose-dependent manner, an effect replicated by micrococcal nuclease digestion. Specific terminal deoxynucleotidyl transferase-(TdT) mediated labeling of 3'-OH ends of DNA nicks corroborated the flow cytometric profiles of propidium iodide-DNA binding where degradation of both 2 and 4 N genomic DNA resulted in a solitary 1N peak presentation. DNA degradation concomitant with cell condensation is seen as an established hallmark of PCD. We further showed that Zn2+ could enhance the generation of hydroxyl free radicals (OH.) by the transition metal vanadium. Glutathione, the cell's main reducing agent, underwent corresponding reduction. The results suggested that Zn supplementation could induce features resembling PCD.
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PMID:Adding Zn2+ induces DNA fragmentation and cell condensation in cultured human Chang liver cells. 936 28

A surgically created canal was used as a reservoir for instillation of snuff into the lower lip of rats for 10 weeks. DNA was isolated and digested with micrococcal nuclease/spleen phosphodiesterase. Polar DNA adducts were detected in all tissues examined when digests were fractionated by high performance liquid chromatography (HPLC), 32P postlabeled, 3' dephosphorylated and analyzed by two-dimensional thin layer chromatography (TLC). DNA adducts derived from aromatic carcinogens were not detected when digests were 32P postlabeled and analyzed by four-dimensional thin layer chromatography. These results suggest that non-aromatic agents initiate carcinogenesis following exposure to snuff. The adduction to DNA in organs of the gastrointestinal tract and the kidneys indicates that snuff usage results in systemic exposure to carcinogens and may contribute to the incidence of neoplasms in organs outside the oral cavity.
Cancer Lett 1997 Dec 16
PMID:Detection of DNA adducts by 32P postlabeling following chronic exposure of rats to snuff. 945 68

Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G(1), G(2), and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene.
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PMID:Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment. 1049 Jun 33


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