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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These studies indicate that SV40T antigen binds the amino terminus of human top1 both in vitro and in vivo. Additional in vitro data suggest that the interaction between these two proteins does not require DNA as an intermediary. Taken together with the finding that the amino terminus of top 1 binds the putative helicase nucleolin, these results implicate helicase binding as a general function of the amino terminus of human top1. Binding of top1 by helicases may be important in the management of structural alterations in DNA produced by helicases. The potential importance of helicase-topoisomerase interactions has been highlighted by recent data indicating that the protein defective in Bloom's syndrome is a helicase with a yeast homologue that is known to bind topoisomerases.
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PMID:A role for the amino terminus of human topoisomerase I. 976 57

Topoisomerases catalyse changes in the topological state of DNA and are required for many aspects of DNA metabolism. While the functions of topoisomerases I and II in eukaryotes are well established, the role of topoisomerase III remains poorly defined. We have identified a gene in the fission yeast Schizosaccharomyces pombe, designated top3 (+), which shows significant sequence similarity to genes encoding topoisomerase III enzymes in other eukaryotic species. In common with murine TOP3 alpha, but in contrast to Saccharomyces cerevisiae TOP3, the S.pombe top3 (+)gene is essential for long-term cell viability. Fission yeast haploid spores containing a disrupted top3 (+)gene germinate successfully, but then undergo only a limited number of cell divisions. Analysis of these top3 mutants revealed evidence of aberrant mitotic chromosome segregation, including the 'cut' phenotype, where septation is completed prior to nuclear division. Consistent with the existence of an intimate association (originally identified in S.cerevisiae ) between topoisomerase III and DNA helicases of the RecQ family, deletion of the rqh1 (+)gene encoding the only known RecQ helicase in S.pombe suppresses lethality in top3 mutants. This conservation of genetic interaction between two widely diverged yeasts suggests that the RecQ family helicases encoded by the Bloom's and Werner's syndrome genes are likely to act in concert with topoisomerase III isozymes in human cells. Our data are consistent with a model in which the association of a RecQ helicase and topoisomerase III is important for facilitating decatenation of late stage replicons to permit faithful chromosome segregation during anaphase.
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PMID:Topoisomerase III is essential for accurate nuclear division in Schizosaccharomyces pombe. 1049 70

The Bloom (BLM) and Werner's (WRN) syndrome proteins may regulate recombination and DNA repair. Using a novel polyclonal antibody to human BLM, we detected the 170-kda BLM antigen in wild-type but not Bloom syndrome cells. BLM was localized to punctate nuclear structures. The level of BLM but not WRN was 3.6 fold-higher in G(1)/S-synchronized fibroblasts than in G(0)-synchronized fibroblasts. BLM-positive cells invariably expressed topoisomerase IIalpha, whereas topoisomerase IIbeta was expressed constitutively. Transfections of BLM deletion mutants demonstrated that the C-terminal domain of BLM mediated nuclear entry and the central helicase domain was necessary for producing the punctate pattern. By subcellular fractionation, BLM was found primarily in high-salt extracts of the nucleoplasm and the nuclear matrix and was enriched in G(1)/S-synchronized cells compared with G(0)-synchronized cells. There was no interaction between BLM and WRN or topoisomerases IIalpha and IIbeta in fibroblasts. These results demonstrate that BLM is targeted to specific nuclear structures and that its expression is enhanced during cell growth. The known nucleolar localization of WRN, its invariant expression during the cell cycle, and the lack of interaction between BLM and WRN suggest distinct roles for BLM and WRN in processes such as DNA repair and recombination.
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PMID:Localization of the Bloom syndrome helicase to punctate nuclear structures and the nuclear matrix and regulation during the cell cycle: comparison with the Werner's syndrome helicase. 1056 3

The RecQ helicase superfamily has been implicated in DNA repair and recombination. At least five human RecQ-related genes exist: RecQ1, BLM, WRN, RecQ4 and RecQ5. Mutations in BLM, WRN and RecQ4 are associated with Bloom, Werner and Rothmund-Thomson syndromes, respectively, involving a predisposition to malignancies and a cellular phenotype that includes increased chromosome instability. RecQ5 is small, containing only a core part of the RecQ helicase, but three isomer transcripts code for small RecQ5alpha (corresponding to the original RecQ5 with 410 amino acids), new large RecQ5beta (991 amino acids) and small RecQ5gamma (435 amino acids) proteins that contain the core helicase motifs. By determining the genomic structure, we found that the three isoforms are generated by differential splicing from the RecQ5 gene that contains at least 19 exons. Northern blot analysis using a RecQ5beta-specific probe indicates that RecQ5beta mRNA is expressed strongly in the testis. Immunocytochemical staining of three N-terminally tagged RecQ5 isomers expressed in 293EBNA cells showed that RecQ5beta migrates to the nucleus and exists exclusively in the nucleoplasm, while the small RecQ5alpha and RecQ5gamma proteins stay in the cytoplasm. Immunoprecipitation and an extended cytochemical experiment suggested that the nucleoplasmic RecQ5beta, like yeast Sgs1 DNA helicase, binds to topoisomerases 3alpha and 3beta, but not to topoisomerase 1. These results predict that RecQ5beta may have an important role in DNA metabolism and may also be related to a distinct genetic disease.
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PMID:Human RecQ5beta, a large isomer of RecQ5 DNA helicase, localizes in the nucleoplasm and interacts with topoisomerases 3alpha and 3beta. 1071 Apr 32

Bloom syndrome (BS) is characterized by genomic instability and cancer susceptibility caused by defects in BLM, a DNA helicase of the RecQ-family (J. German and N. A. Ellis, The Genetic Basis of Human Cancer, pp. 301-316, 1998). RecQ helicases and topoisomerase III proteins interact physically and functionally in yeast (S. Gangloff et al., Mol. Cell. Biol., 14: 8391-8398, 1994) and in Escherichia coli can function together to enable passage of double-stranded DNA (F. G. Harmon et al., Mol. Cell, 3: 611-620, 1999). We demonstrate in somatic and meiotic human cells an association between BLM and topoisomerase IIIalpha. These proteins colocalize in promyelocytic leukemia protein nuclear bodies, and this localization is disrupted in BS cells. Thus, mechanisms by which RecQ helicases and topoisomerase III proteins cooperate to maintain genomic stability in model organisms likely apply to humans.
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PMID:Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells. 1072 66

Bloom's syndrome is a rare genetic disorder associated with loss of genomic integrity and a large increase in the incidence of many types of cancer at an early age. The Bloom's syndrome gene product, BLM, belongs to the RecQ family of DNA helicases, which also includes the human Werner's and Rothmund-Thomson syndrome gene products and the Sgs1 protein of Saccharomyces cerevisiae. This family shows strong evolutionary conservation of protein structure and function. Previous studies have shown that Sgs1p interacts both physically and genetically with topoisomerase III. Here, we have investigated whether this interaction has been conserved in human cells. We show that BLM and hTOPO IIIalpha, one of two human topoisomerase III homologues, co-localize in the nucleus of human cells and can be co-immunoprecipitated from human cell extracts. Moreover, the purified BLM and hTOPO IIIalpha proteins are able to bind specifically to each other in vitro, indicating that the interaction is direct. We have mapped two independent domains on BLM that are important for mediating the interaction with hTOPO IIIalpha. Furthermore, through characterizing a genetic interaction between BLM and TOP3 in S. cerevisiae, we have identified a functional role for the hTOPO IIIalpha interaction domains in BLM.
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PMID:The Bloom's syndrome gene product interacts with topoisomerase III. 1073 15

The Saccharomyces cerevisiae gene SGS1 encodes a DNA helicase that shows homology to the Escherichia coli protein RecQ and the products of the BLM and WRN genes in humans, which are defective in Bloom's and Werner's syndrome, respectively. Recently, it has been proposed that this helicase is involved in maintaining the integrity of the rDNA and that loss of Sgs1 function leads to accelerated aging. Sgs1 has been isolated on the basis of its genetic interaction with both topoisomerase I and topoisomerase III, as well as in a two-hybrid screen for proteins that interact with the C-terminal portion of topoisomerase II. We have defined the minimal structural elements of Sgs1 required for its interactions with the three topoisomerases, and demonstrate that the complex phenotypes associated with sgs1 mutants are a consequence of a dysfunctional Sgs1-Top3 complex. We also report that the synthetic relationship between mutations in SGS1 and SRS2, which encodes another helicase implicated in recombinational repair, likewise result from a dysfunctional Sgs1-Top3 interaction. Our findings indicate that Sgs1 may act on different DNA structures depending on the activity of topoisomerase I, Srs2 and topoisomerase III.
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PMID:Genetic analysis of the Saccharomyces cerevisiae Sgs1 helicase defines an essential function for the Sgs1-Top3 complex in the absence of SRS2 or TOP1. 1101 37

Deficiency in a helicase of the RecQ family is found in at least three human genetic disorders associated with cancer predisposition and/or premature ageing. The RecQ helicases encoded by the BLM, WRN and RECQ4 genes are defective in Bloom's, Werner's and Rothmund-Thomson syndromes, respectively. Cells derived from individuals with these disorders in each case show inherent genomic instability. Recent studies have demonstrated direct interactions between these RecQ helicases and human nuclear proteins required for several aspects of chromosome maintenance, including p53, BRCA1, topoisomerase III, replication protein A and DNA polymerase delta. Here, we review this network of protein interactions, and the clues that they present regarding the potential roles of RecQ family members in DNA repair, replication and/or recombination pathways.
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PMID:DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. 1125 7

Targeted gene disruption in the murine TOP3beta gene-encoding DNA topoisomerase IIIbeta was carried out. In contrast to the embryonic lethality of mutant mice lacking DNA topoisomerase IIIalpha, top3beta(-/-) nulls are viable and grow to maturity with no apparent defects. Mice lacking DNA topoisomerase IIIbeta have a shorter life expectancy than their wild-type littermates, however. The mean lifespan of the top3beta(-/-) mice is about 15 months, whereas that of their wild-type littermates is longer than 2 years. Mortality of the top3beta(-/-) nulls appears to correlate with lesions in multiple organs, including hypertrophy of the spleen and submandibular lymph nodes, glomerulonephritis, and perivascular infiltrates in various organs. Because the DNA topoisomerase III isozymes are likely to interact with helicases of the RecQ family, enzymes that include the determinants of human Bloom, Werner, and Rothmund-Thomson syndromes, the shortened lifespan of top3beta(-/-) mice points to the possibility that the DNA topoisomerase III isozymes might be involved in the pathogenesis of progeroid syndromes caused by defective RecQ helicases.
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PMID:Mice lacking DNA topoisomerase IIIbeta develop to maturity but show a reduced mean lifespan. 1133 80

The Saccharomyces cerevisiae SGS1 gene is a member of the RecQ family of ATP-dependent DNA helicases, which includes the human WRN, BLM and RECQ4 genes. Mutations in the WRN gene cause the human premature ageing disorder, Werner's syndrome. Deletion of the SGS1 gene also causes premature ageing in yeast, suggesting that the molecular mechanisms of cellular ageing may be evolutionarily conserved. To investigate the role of the RecQ helicase domain in ageing, a point mutation (SGS1 K(706)-->A) known to eliminate the DNA helicase activity of Sgs1p was constructed. This mutant allele failed to rescue the premature ageing of the sgs1Delta strain, demonstrating that Sgs1p DNA helicase activity is required for a normal lifespan. In contrast, the SGS1 K(706)-->A allele was sufficient to rescue the hypersensitivity of the sgs1Delta strain to topoisomerase inhibitors, but not other genotoxic agents. These findings support the idea that Sgs1p fulfils multiple cellular functions, and that DNA helicase activity is dispensable for some of these (e.g. functional interaction with topoisomerases), but essential for others (e.g. longevity).
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PMID:The DNA helicase activity of yeast Sgs1p is essential for normal lifespan but not for resistance to topoisomerase inhibitors. 1138 27


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