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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor BRCA1 has an important function in the maintenance of genomic stability. Increasing evidence suggests that BRCA1 regulates cell cycle checkpoints and DNA repair after DNA damage. However, little is known about its normal function in the absence of DNA damage. Here we show that BRCA1 interacts and colocalizes with topoisomerase IIalpha in S phase cells. Similar to cells treated with the topoisomerase IIalpha inhibitor ICRF-193, BRCA1-deficient cells show lagging chromosomes, indicating a defect in DNA decatenation and chromosome segregation. More directly, BRCA1 deficiency results in defective DNA decatenation in vitro. Finally, topoisomerase IIalpha is ubiquitinated in a BRCA1-dependent manner, and topoisomerase IIalpha ubiquitination correlates with higher DNA decatenation activity. Together these results suggest an important role of BRCA1 in DNA decatenation and reveal a previously unknown function of BRCA1 in the maintenance of genomic stability.
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PMID:BRCA1 participates in DNA decatenation. 1596 87

Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease-associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase IIalpha poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.
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PMID:BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene. 1628 14

Topoisomerase II is essential for cell proliferation and survival and has been a target of various anticancer drugs. ICRF-193 has long been used as a catalytic inhibitor to study the function of topoisomerase II. Here, we show that ICRF-193 treatment induces DNA damage signaling. Treatment with ICRF-193 induced G2 arrest and DNA damage signaling involving gamma-H2AX foci formation and CHK2 phosphorylation. DNA damage by ICRF-193 was further demonstrated by formation of the nuclear foci of 53BP1, NBS1, BRCA1, MDC1, and FANCD2 and increased comet tail moment. The DNA damage signaling induced by ICRF-193 was mediated by ATM and ATR and was restricted to cells in specific cell cycle stages such as S, G2, and mitosis including late and early G1 phases. Downstream signaling of ATM and ATR involved the phosphorylation of CHK2 and BRCA1. Altogether, our results demonstrate that ICRF-193 induces DNA damage signaling in a cell cycle-dependent manner and suggest that topoisomerase II might be essential for the progression of the cell cycle at several stages including DNA decondensation.
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PMID:Cell cycle-dependent DNA damage signaling induced by ICRF-193 involves ATM, ATR, CHK2, and BRCA1. 1663 Jun 10

Besides BRCA1 and BRCA2 other genes are also likely to be involved in hereditary predisposition to breast and/or ovarian cancer. TopBP1 (topoisomerase IIbeta binding protein 1) displays sequence homology as well as functional similarities with BRCA1, and the two proteins have been suggested to function partly in the same cellular processes. TopBP1 is crucial for DNA damage and replication checkpoint controls. Based on its biological significance, we reasoned that TopBP1 is a plausible susceptibility gene for hereditary breast and/or ovarian cancer and therefore screened affected index cases from 125 Finnish cancer families for germline changes by conformation sensitive gel electrophoresis (CSGE). Altogether 19 different sequence alterations were detected. A novel heterozygous Arg309Cys variant was observed at elevated frequency in the familial cancer cases compared to healthy controls (15.2% versus 7.0%; P=0.002). Current results suggest that Arg309Cys is a commonly occurring germline alteration possibly associated with a slightly increased breast and/or ovarian cancer risk. This is the first study reporting mutation screening of the TopBP1 gene in a familial cancer material.
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PMID:Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer. 1693 Sep 91

We investigated the physical association of the DNA topoisomerase IIbeta binding protein 1 (TopBP1), involved in DNA replication and repair but also in regulation of apoptosis, with poly(ADP-ribose) polymerase-1 (PARP-1). This enzyme plays a crucial role in DNA repair and interacts with many DNA replication/repair factors. It was shown that the sixth BRCA1 C-terminal (BRCT) domain of TopBP1 interacts with a protein fragment of PARP-1 in vitro containing the DNA-binding and the automodification domains. More significantly, the in vivo interaction of endogenous TopBP1 and PARP-1 proteins could be shown in HeLa-S3 cells by co-immunoprecipitation. TopBP1 and PARP-1 are localized within overlapping regions in the nucleus of HeLa-S3 cells as shown by immunofluorescence. Exposure to UVB light slightly enhanced the interaction between both proteins. Furthermore, TopBP1 was detected in nuclear regions where poly(ADP-ribose) (PAR) synthesis takes place and is ADP-ribosylated by PARP-1. Finally, cellular (ADP-ribosyl)ating activity impairs binding of TopBP1 to Myc-interacting zinc finger protein-1 (Miz-1). The results indicate an influence of post-translational modifications of TopBP1 on its function during DNA repair.
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PMID:The DNA topoisomerase IIbeta binding protein 1 (TopBP1) interacts with poly (ADP-ribose) polymerase (PARP-1). 1734 Jun 32

The function of BRCA1 and BRCA2 in DNA repair could affect the sensitivity of cells to cytotoxic agents, and would therefore be an important component of planning therapy for breast and ovarian cancers. Previously, both BRCA1- and BRCA2-deficient tumors were shown to be sensitive to mitomycin C, and the mechanism was presumed to be a defect in the repair of interstrand crosslinks by homologous recombination. Here, we show that both BRCA1 and BRCA2 determine the sensitivity to the cytotoxic drug, etoposide, using genetic complementation of BRCA-deficient cells. Etoposide is known to bind to topoisomerase II and prevent the resolution of the "cleavable complex," in which one DNA duplex is passed through a second duplex. The specificity of this BRCA-dependent sensitivity was confirmed by the use of aclarubicin, which is a catalytic inhibitor of topoisomerase II and prevents the formation of the cleavable complex. In the presence of aclarubicin, the differential sensitivity of BRCA-proficient and BRCA-deficient cells was lost. Thus, etoposide requires the presence of topoisomerase II to show specific sensitization in the absence of the function of BRCA1 or BRCA2. We conclude that homologous recombination is used in the repair of DNA damage caused by topoisomerase II poisons. Overall, these results suggest that etoposide is a potentially useful drug in the treatment of BRCA-deficient human cancers.
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PMID:BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. 1767 Nov 73

TopBP1 (topoisomerase IIbeta-binding protein 1) is a BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminal]-domain-rich protein that is structurally and functionally conserved throughout eukaryotic organisms. It is required for the initiation of DNA replication and for DNA repair and DNA damage signalling. Experiments with fission yeast and Xenopus revealed that the TopBP1 homologues of these organisms are required for chromatin loading of the replication protein Cdc45 (cell division cycle 45). To improve our understanding of the physiological functions of human TopBP1, we investigated the interplay between human TopBP1 and Cdc45 proteins in synchronized HeLa-S3 cells. Using GST (glutathione transferase) pull-down and co-immunoprecipitation techniques, we showed a direct interaction between TopBP1 and Cdc45 in vitro and in vivo. The use of deletion mutants in GST pull-down assays identified the first and second as well as the sixth BRCT domains of TopBP1 to be responsible for the functional interaction with Cdc45. Moreover, the interaction between Cdc45 and the first and second BRCT domains of TopBP1 inhibited their transcriptional activation both in yeast and mammalian one-hybrid systems. Both proteins interacted exclusively at the G(1)/S boundary of cell cycle; only weak interaction could be found at the G(2)/M boundary. The overexpression of the sixth BRCT domain led to diminished loading of Cdc45 on to chromatin. These results suggest that human TopBP1 is involved in the formation of the initiation complex of replication in human cells and is required for the recruitment of Cdc45 to origins of DNA replication.
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PMID:Characterization of the interaction between the human DNA topoisomerase IIbeta-binding protein 1 (TopBP1) and the cell division cycle 45 (Cdc45) protein. 1788 56

Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000 x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.
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PMID:PARP inhibitor development for systemic cancer targeting. 1789 12

Topoisomerase IIalpha is known to be critically involved in both cell proliferation and cell death. The mechanisms responsible for stress-dependent topoisomerase IIalpha alterations, however, remain unclear. This study focused on the behavior of topoisomerase IIalpha in response to oxidative stress induced by hydrogen peroxide (H(2)O(2)). The catalytic activity of topoisomerase IIalpha in MOLT-4 cells treated with H(2)O(2) decreased in parallel with the alteration of topoisomerase IIalpha expression. The ubiquitination of topoisomerase IIalpha was dependent on oxidative stress. BRCA1, a tumor-suppressor gene, appeared to be involved in these alterations in topoisomerase IIalpha. Furthermore, the retinoblastoma protein (pRb) was required for the ubiquitination of topoisomerase IIalpha by BRCA1. We conclude that the functions of topoisomerase IIalpha are regulated by ubiquitination on exposure to oxidative stress.
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PMID:BRCA1-mediated ubiquitination inhibits topoisomerase II alpha activity in response to oxidative stress. 1816 55

Epirubicin exerts its anti-tumor effect through binding to topoisomerase IIalpha (TOP2A) and inducing DNA double-strand breaks. BRCA1 is involved in the repair of these breaks. We investigated the relationship between TOP2A or BRCA1 immunohistochemical expression and pathological response in 108 primary breast cancers treated with epirubicin-based regimens. The pCR (pathological complete response) rate for TOP2A-positive (17%) was significantly (P < 0.005) higher than for TOP2A-negative (2%), while the pCR rate for BRCA1-negative (11%) was non-significantly higher than for BRCA1-positive (5%). The pCR rate of TOP2A-positive and BRCA1-negative (30%) was significantly higher than for TOP2A-negative and BRCA1-positive (3%; P < 0.05), or TOP2A-negative and BRCA1-negative (0%; P < 0.005). The TOP2A-positive and BRCA1-negative phenotype associates with a favorable response to epirubicin-based regimens.
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PMID:Topoisomerase IIalpha-positive and BRCA1-negative phenotype: association with favorable response to epirubicin-based regimens for human breast cancers. 1828 Jun 44


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