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)

Excision repair of damage due to ultraviolet radiation, N-acetoxy-2-acetyl-aminofluorene and a combination of both agents was studied in normal human fibroblasts and various cells from cancer prone patients (ataxia telangiectasia, Fanconi's anemia, Cockayne syndrome and Bloom's syndrome). Three methods giving similar results were used: unscheduled DNA synthesis by radioautography, photolysis of bromodeoxyuridine incorporated into parental DNA during repari, and loss of sites sensitive to an ultraviolet endonuclease. All cell lines were proficient in repair of ultraviolet and acetoxy acetylaminofluorene damage and at saturation doses of both agents repair was additive. We interpret these data as indicating that the rate limiting step in excision repair of ultraviolet and acetoxy acetylaminofluorene is different and that there are different enzyme(s) working on incision of both types of damages.
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PMID:Excision repair in ataxia telangiectasia, Fanconi's anemia, Cockayne syndrome, and Bloom's syndrome after treatment with ultraviolet radiation and N-acetoxy-2-acetylaminofluorene. 73 87

Ataxia telangiectasia, Bloom's syndrome and normal fibroblasts were compared as to the capacity of their cellular extracts to enhance the priming activity of gamma-irradiated colicin E1 DNA for purified DNA polymerase. It was found that an ataxia strain had substantially lower, and a Bloom's syndrome strain had slightly lower capacity than a normal strain; while the activities of apurinic site specific endonuclease in these extracts were comparable.
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PMID:DNA repair enzymes in ataxia telangiectasia and Bloom's syndrome fibroblasts. 92 14

We have studied repair of ultraviolet light (UV)-induced damage in a strain of Bloom's syndrome cells which we have shown to be defective in host cell reactivation of UV-irradiated herpes simplex virus. Excision repair was monitored by following loss of sensitivity of DNA in permeabilized cells to digestion by the Micrococcus luteus UV endonuclease preparation. The Bloom's syndrome fibroblasts apparently removed endonuclease-sensitive sites from the DNA slightly less efficiently than did normal strains. After 24 hr, 38% of the sites remained in the Bloom's syndrome cells in comparison with 16% in normal fibroblasts. DNA newly synthesized in UV-irradiated Bloom's syndrome cells sedimented less far into alkaline sucrose gradients than did DNA from similarly treated normal cells. In other respects, including the effect of caffeine exposure, DNA synthesis in Bloom's syndrome cells was indistinguishable from that in normal cells. We were therefore able to detect only minor defects in the repair of UV-induced damage in Bloom's syndrome fibroblasts. This is consistent with the normal survival exhibited by these cells. The defect in excision repair may, however, be sufficient to allow the cellular repair capacity to become saturated at high infecting multiplicities of UV-irradiated herpes simplex virus.
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PMID:Excision of ultraviolet damage and the effect of irradiation on DNA synthesis in a strain of Bloom's syndrome fibroblasts. 625 83

Sensitivities to UV and mitomycin C (MC) of fibroblasts obtained from 3 Japanese patients with Bloom's syndrome (BS) were studied. One BS strain was more sensitive to UV than normal cells only in colony-forming ability. Other responses to UV, such as unscheduled DNA synthesis, host-cell reactivation and removal of UV-endonuclease-susceptible sites, were normal in all 3 strains. These BS strains were more sensitive to MC than were normal cells. However, the amounts of unscheduled DNA synthesis after treatment with MC in BS cells did not differ from those in normal cells.
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PMID:DNA repair in Bloom's syndrome fibroblasts after UV irradiation or treatment with mitomycin C. 720 83

Cds1, a serine/threonine kinase, enforces the S-M checkpoint in the fission yeast Schizosaccharomyces pombe. Cds1 is required for survival of replicational stress caused by agents that stall replication forks, but how Cds1 performs these functions is largely unknown. Here we report that the forkhead-associated-1 (FHA1) protein-docking domain of Cds1 interacts with Mus81, an evolutionarily conserved damage tolerance protein. Mus81 has an endonuclease homology domain found in the XPF nucleotide excision repair protein. Inactivation of mus81 reveals a unique spectrum of phenotypes. Mus81 enables survival of deoxynucleotide triphosphate starvation, UV radiation, and DNA polymerase impairment. Mus81 is essential in the absence of Bloom's syndrome Rqh1 helicase and is required for productive meiosis. Genetic epistasis studies suggest that Mus81 works with recombination enzymes to properly replicate damaged DNA. Inactivation of Mus81 triggers a checkpoint-dependent delay of mitosis. We propose that Mus81 is involved in the recruitment of Cds1 to aberrant DNA structures where Cds1 modulates the activity of damage tolerance enzymes.
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PMID:Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. 1107 77

The RecQ DNA helicases, human BLM and yeast Sgs1, form a complex with topoisomerase III (Top3) and are thought to act during DNA replication to restart forks that have paused due to DNA damage or topological stress. We have shown previously that yeast cells lacking SGS1 or TOP3 require MMS4 and MUS81 for viability. Here we show that Mms4 and Mus81 form a heterodimeric structure-specific endonuclease that cleaves branched DNA. Both subunits are required for optimal expression, substrate binding, and nuclease activity. Mms4 and Mus81 are conserved proteins related to the Rad1-Rad10 (XPF/ERCC1) endonuclease required for nucleotide excision repair (NER). However, the Mms4-Mus81 endonuclease is 25 times more active on branched duplex DNA and replication fork substrates than simple Y-forms, the preferred substrate for the NER complexes. We also present genetic data that indicate a novel role for Mms4-Mus81 in meiotic recombination. Our results suggest that stalled replication forks are substrates for Mms4-Mus81 cleavage-particularly in the absence of Sgs1 or BLM. Repair of this double-strand break (DSB) by homologous recombination may be responsible for the elevated levels of sister chromatid exchange (SCE) found in BLM(-/-) cells.
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PMID:Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease. 1164 Dec 78

Microcalorimetry and UV-vis spectroscopy were used to conduct thermodynamic and kinetic investigations of the scission of calf thymus DNA catalyzed by bleomycin A5 (BLM-A5) in the presence of ferrous ion and oxygen. The molar reaction enthalpy for the cleavage, the Michaelis-Menten constant for calf thymus DNA and the turnover number of BLM-A5 were calculated by a novel thermokinetic method for an enzyme-catalyzed reaction to be -577 +/- 19 kJ.mol-1, 20.4 +/- 3.8 microm and 2.28 +/- 0.49 x 10-2 s-1, respectively, at 37.0 degrees C. This DNA cleavage was a largely exothermic reaction. The catalytic efficiency of BLM-A5 is of the same order of magnitude as that of lysozyme but several orders of magnitude lower than those of TaqI restriction endonuclease, NaeI endonuclease and BamHI endonuclease. By comparing the molar enthalpy change for the cleavage of calf thymus DNA induced by BLM-A5 with those for the scission of calf thymus DNA mediated by adriamycin and by (1,10-phenanthroline)-copper, it was found that BLM-A5 possessed the highest DNA cleavage efficiency among these DNA-damaging agents. These results suggest that BLM-A5 is not as efficient as a DNA-cleaving enzyme although the cleavage of DNA by BLM-A5 follows Michaelis-Menten kinetics. Binding of BLM-A5 to calf thymus DNA is driven by a favorable entropy increase with a less favorable enthalpy decrease, in line with a partial intercalation mode involved in BLM-catalyzed breakage of DNA.
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PMID:Thermodynamics and kinetics of the cleavage of DNA catalyzed by bleomycin A5. 1207 47

The RecQ DNA helicases human BLM and yeast Sgs1 interact with DNA topoisomerase III and are thought to act on stalled replication forks to maintain genome stability. To gain insight into this mechanism, we previously identified SLX1 and SLX4 as genes that are required for viability and for completion of rDNA replication in the absence of SGS1-TOP3. Here we show that SLX1 and SLX4 encode a heteromeric structure-specific endonuclease. The Slx1-Slx4 nuclease is active on branched DNA substrates, particularly simple-Y, 5'-flap, or replication fork structures. It cleaves the strand bearing the 5' nonhomologous arm at the branch junction and generates ligatable nicked products from 5'-flap or replication fork substrates. Slx1 is the founding member of a family of proteins with a predicted URI nuclease domain and PHD-type zinc finger. This subunit displays weak structure-specific endonuclease activity on its own, is stimulated 500-fold by Slx4, and requires the PHD finger for activity in vitro and in vivo. Both subunits are required in vivo for resistance to DNA damage by methylmethane sulfonate (MMS). We propose that Sgs1-Top3 acts at the termination of rDNA replication to decatenate stalled forks, and, in its absence, Slx1-Slx4 cleaves these stalled forks.
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PMID:Slx1-Slx4 is a second structure-specific endonuclease functionally redundant with Sgs1-Top3. 1283 95

Mus81 is a highly conserved substrate specific endonuclease. Human Mus81 cleaves Holliday junctions, replication forks, and 3' flap substrates in vitro, suggesting a number of possible in vivo functions. We show here that the abundance of human Mus81 peaks in S-phase and remains high in cells that have completed DNA replication and that Mus81 is a predominantly nuclear protein, with super accumulation in nucleoli. Two RecQ related DNA helicases BLM and WRN that are required for recombination repair in human cells colocalize with Mus81 in nucleoli. However, the nucleolar retention of Mus81 is not dependent on the presence of BLM or WRN, or on ongoing transcription. Mus81 is recruited to localized regions of UV damage in S-phase cells, but not in cells that are blocked from replicating DNA or that have completed replication. The retention of human Mus81 at regions of UV-induced damage specifically in S-phase cells suggest that the enzyme is recruited to the sites at which replication forks encounter damaged DNA. The nucleolar concentration of Mus81 suggests that it is required to repair problems that arise most frequently in the highly repetitive nucleolar DNA. Together these data support a role for Mus81 in recombination repair in higher eukaryotes.
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PMID:Mus81 endonuclease localizes to nucleoli and to regions of DNA damage in human S-phase cells. 1463 71

Bloom's syndrome (BS) is a rare autosomal recessive genetic disorder associated with genomic instability and an elevated risk of cancer. Cellular features of BS include an accumulation of abnormal replication intermediates and increased sister chromatid exchange. Although it has been suggested that the underlying defect responsible for hyper-recombination in BS cells is a temporal delay in the maturation of DNA replication intermediates, the precise role of the BS gene product, BLM, in DNA metabolism remains elusive. We report here a novel interaction of the BLM protein with the human 5'-flap endonuclease/5'-3' exonuclease (FEN-1), a genome stability factor involved in Okazaki fragment processing and DNA repair. BLM protein stimulates both the endonucleolytic and exonucleolytic cleavage activity of FEN-1 and this functional interaction is independent of BLM catalytic activity. BLM and FEN-1 are associated with each other in human nuclei as shown by their reciprocal co-immunoprecipitation from HeLa nuclear extracts. The BLM-FEN-1 physical interaction is mediated through a region of the BLM C-terminal domain that shares homology with the FEN-1 interaction domain of the Werner syndrome protein, a RecQ helicase family member homologous to BLM. This study provides the first evidence for a direct interaction of BLM with a human nucleolytic enzyme. We suggest that functional interactions between RecQ helicases and Rad2 family nucleases serve to process DNA substrates that are intermediates in DNA replication and repair.
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PMID:Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. 1468 84


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