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evolution
genes encoding topoisomerase III enzymes are highly conserved in evolution from bacteria to human
evolution
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activity comparison of two related type IA topoisomerases, Topo I and Topo III: Topo I initiates relaxation sooner than Topo III. and for most substrates, the pauses between relaxation runs catalyzed by Topo I are spaced by only a few seconds, whereas Topo III paused for tens of seconds in between relaxation runs
evolution
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Escherichia coli topoisomerase I belongs to type I subfamily DNA topoisomerases. YrdD, a homolog of the C-terminal zinc binding region of Escherichia coli topoisomerase I, is highly conserved among proteobacteria and enterobacteria
evolution
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type IA enzymes are ubiquitous. They are present in bacteria, archaea and eukarya. Although all type IA topoisomerases are related at the sequence, structure and mechanism levels, different type IA enzymes do not participate in the same cellular processes. For topoisomerase I in DNA relaxation reaction, the pauses are short and the relaxation runs are slow, while topoisomerase III behaves the opposite way: the the pauses are long and the relaxation runs are fast. The combination of these two general features results in topoisomerase I having a higher overall relaxation rate than topoisomerase III
evolution
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genes encoding topoisomerase III enzymes are highly conserved in evolution from bacteria to human
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malfunction
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eukaryotic top1 is affected by the modification of DNA by antitumor cisplatin
malfunction
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selective inhibition of Cdc2-like kinases and DNA topoisomerase I elicite distinct changes in TF biosynthesis in TNF-alpha-stimulated endothelial cells, which impact endothelial procoagulant activity, overview
malfunction
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Top1-deficient cells accumulate stalled replication forks and chromosome breaks in S phase resulting in supercoiled DNA and altered RNA splicing, breaks occur preferentially at gene-rich regions of the genome
malfunction
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accumulation of cleavage complex formed by inactivated MtTOP1 is lethal for the cell
malfunction
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enzyme inhibition activates transcriptional Cdk (Cdk9 and/or Cdk7) activity leading o the hyperphosphorylation of the CTD of the largest subunit of RNA polymerase II
malfunction
the phenotypic consequences of loss of topoisomerase III function are generally quite severe
malfunction
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mitochondria are dysfunctional in mitochondrial isozyme Top1mt-deficient cells, the ATP content is 2fold less in Top1mt-/- compared to wild-type cells, confirming dysfunctional respiratory chain in Top1mt-/- cells. The mutant cells also show Increases of fatty acid oxidation and lipogenesis. Isozyme Top1mt deficiency leads to increased glycolytic activity
malfunction
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the enzyme depletion inhibits growth, blocks sporulation, and affects septation and chromosome condensation. But sporulation in the TopA-depleted strain can be partially restored by deletion of parB. Depletion of the TopA protein affects the secondary metabolism of Streptomyces coelicolor, leading to overproduction of actinorhodin
malfunction
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TOP1 mutations are involved in the development of SN38 resistance. Mutation of one of residues L617, R621, and E710, important for the functionality of the linker, is sufficient to alter or modulate its flexibility. DNA double strand break formation is reduced in SN38 resistant HCT116 cells. Colorectal cancer patients and SN38 resistant HCT116 clones phemotypes, overview
malfunction
topA deletion mutant strain DELTAtopA grows more slowly than the wild-type strain. The doubling time of the mutant is 11.9 h, as compared to 7.4 h for the wild-type strain, when both strains are grown in the rich medium at 75°C. The enzyme may not serve a critical role in the adaptation of thermophilic archaea to growth at high temperature
malfunction
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the phenotypic consequences of loss of topoisomerase III function are generally quite severe
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malfunction
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topA deletion mutant strain DELTAtopA grows more slowly than the wild-type strain. The doubling time of the mutant is 11.9 h, as compared to 7.4 h for the wild-type strain, when both strains are grown in the rich medium at 75°C. The enzyme may not serve a critical role in the adaptation of thermophilic archaea to growth at high temperature
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metabolism
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the mycobacterial topoisomerase I physically interacts with its ribokinase both in vitro and in vivo with opposite effects on their respective function, overview. While the interaction between the two proteins inhibits the ability of TopA to relax supercoiled DNA, it stimulates ribokinase activity as a regulatory strategy for efficient utilization of D-ribose
metabolism
the mycobacterial topoisomerase I physically interacts with its ribokinase both in vitro and in vivo with opposite effects on their respective function, overview. While the interaction between the two proteins inhibits the ability of TopA to relax supercoiled DNA, it stimulates ribokinase activity as a regulatory strategy for efficient utilization of D-ribose
metabolism
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the mycobacterial topoisomerase I physically interacts with its ribokinase both in vitro and in vivo with opposite effects on their respective function, overview. While the interaction between the two proteins inhibits the ability of TopA to relax supercoiled DNA, it stimulates ribokinase activity as a regulatory strategy for efficient utilization of D-ribose
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physiological function
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Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor, TF,via phosphorylation of serine/arginine-rich proteins
physiological function
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DNA topoisomerase enzymes regulate the topological state of DNA that is crucial for initiation and elongation during DNA synthesis
physiological function
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DNA topoisomerase I is ubiquitous and essential in mammals and is involved in tumor growth
physiological function
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the enzyme is of fundamental importance to processes such as replication, recombination and transcription
physiological function
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topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy, Topo I expression is associated with a reduced risk of death, overview
physiological function
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topoisomerase I is a key enzyme in functioning at the interface between DNA replication, transcription and mRNA maturation. Top1 suppresses genomic instability in mammalian cells by preventing a conflict between transcription and DNA replication, it prevents replication fork collapse by suppressing the formation of R-loops in an ASF/SF2-dependent manner
physiological function
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as a result of its catalytic mechanism, topoisomerase I plays an important role in removing positive DNA supercoils that accumulate ahead of replication forks and transcription complexes. Cleavage events most likely to generate permanent genomic damage are those that occur ahead of DNA tracking systems. The human enzyme maintains higher levels of cleavage with positively as opposed to negatively supercoiled substrates in the absence or presence of anticancer drugs. Sites of topoisomerase I-mediated DNA cleavage do not appear to be affected by supercoil geometry, but rates of ligation are slower with positively supercoiled substrates
physiological function
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bacterial topoisomerase I plays a major role in preventing excessive negative supercoiling of DNA and its function is actively involved in the SOS response to antibiotics and stress challenge. Cell killing initiated by the topoisomerase I cleavage complex is enhanced by antibiotics and the host response. During rapid transcription at gene loci induced by the stress response, movement of the RNA polymerase complex leads to increased negative supercoiling behind the complex. Topoisomerase I is needed to prevent hypernegative supercoiling and R-loop formation, which would otherwise inhibit the expression of the stress response genes. Topoisomerase I function is required for efficient transcriptional activation of the recA and dinD1 promoters during the Escherichia coli SOS response to trimethoprim and mitomycin C
physiological function
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c-myc is a key regulator for nuclear-encoded mitochondrial genes including mitochondrial isozyme TOP1mt
physiological function
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human topoisomerase I shows transient nicking of double-stranded DNA. Because of this activity, topo I is a main nuclear swivelase responsible for relieving a torsional stress that appears in DNA during transcription, replication, and chromatin condensation. The activity is also used to remove ribonucleotides incorporated during DNA replication and not deleted by the repair system. Because of the kinase activity of topo I, it influences alternative splicing of several transcripts. Both DNA relaxation and phosphorylation activities of topo I are also cooperating in preventing a conflict between transcription and DNA replication. Both activities do not work at the same time: DNA, a substrate for DNA relaxation, inhibits the kinase reaction, whereas both a protein substrate for the kinase activity and ATP inhibit DNA nicking
physiological function
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reverse gyrase is a DNA topoisomerase, specific to microorganisms living at high temperatures, which comprises a type IA topoisomerase fused to an SF2 helicase-like module and catalyzes ATP hydrolysis-dependent DNA positive supercoiling. Reverse gyrase is likely involved in regulation of DNA structure and stability and might also participate in the cell response to DNA damage
physiological function
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topoisomerase I is recruited to ParB complexes and is required for proper chromosome organization during Streptomyces coelicolor sporulation, overview
physiological function
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topoisomerase I relaxes supercoiled DNA during cell division
physiological function
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topoisomerases are the enzymes responsible for maintaining the supercoiled state of DNA in the cell and also for many other DNA-topology-associated reactions. Type IA enzymes alter DNA topology by breaking one DNA strand and passing another strand or strands through the break
physiological function
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DANN topoisomerase I is a critical DNA-nicking enzyme involved in the process of cell-specific, ligand-driven enhancer activation. The enzyme occupies androgen receptor-enhancers KLK3 and KLK2 and affects the transcriptional program of the prostate cancer cell line LNCaP
physiological function
the enzyme is required for the termination of floral stem cell maintenance and is required for the repression of WUS expression in flower development. The enzyme decreases nucleosome density which probably allows the binding of factors that either recruit polycomb group proteins or counteract polycomb group-mediated regulation
physiological function
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the enzyme catalyzes the relaxation of DNA supercoils
physiological function
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the enzyme is required for stem cell regulation in shoot and floral meristems as well as adaptive response to light and flower development
physiological function
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the enzyme modulates the replication process via R-loop formation
physiological function
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reverse gyrase is a DNA topoisomerase, specific to microorganisms living at high temperatures, which comprises a type IA topoisomerase fused to an SF2 helicase-like module and catalyzes ATP hydrolysis-dependent DNA positive supercoiling. Reverse gyrase is likely involved in regulation of DNA structure and stability and might also participate in the cell response to DNA damage
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physiological function
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bacterial topoisomerase I plays a major role in preventing excessive negative supercoiling of DNA and its function is actively involved in the SOS response to antibiotics and stress challenge. Cell killing initiated by the topoisomerase I cleavage complex is enhanced by antibiotics and the host response. During rapid transcription at gene loci induced by the stress response, movement of the RNA polymerase complex leads to increased negative supercoiling behind the complex. Topoisomerase I is needed to prevent hypernegative supercoiling and R-loop formation, which would otherwise inhibit the expression of the stress response genes. Topoisomerase I function is required for efficient transcriptional activation of the recA and dinD1 promoters during the Escherichia coli SOS response to trimethoprim and mitomycin C
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additional information
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camptothecin is a selective inhibitor of DNA topoisomerase I. Camptothecin activates the transcription of low-abundance antisense RNAs at the HIF-1alpha gene locus in human cancer cells in a Topoisomerase I-dependent manner, likely due to sustained drug interference with transcription regulation mechanisms leading to a more open chromatin conformation and de-repression/activation of antisense transcription
additional information
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enzyme model showing that the second site capture might account for DNA crossover binding, nucleation of DNA synapsis, and plectonemic supercoiling within the synaptic filament in TopIB enzyme with both DNA sites filled, overview
additional information
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inhibition of topoisomerase I prevents chromosome breakage at common fragile sites. Polymerase-helicase uncoupling is a key initial event in this process
additional information
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intercalators enhance topoisomerase I-mediated cleavage of negatively supercoiled substrates but not positively supercoiled or linear DNA. These compounds act by altering the perceived topological state of the double helix, making underwound DNA appear to be overwound to the enzyme, acting like topological poisons of topoisomerase I
additional information
LdTopIIIbeta suppresses the yeast top3DELTA slow-growth phenotype. The C-terminal domain of LdTopIIIbeta is essential for in vivo complementation
additional information
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LdTopIIIbeta suppresses the yeast top3DELTA slow-growth phenotype. The C-terminal domain of LdTopIIIbeta is essential for in vivo complementation
additional information
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many antibacterial and anticancer drugs initiate cell killing by trapping the covalent complexes formed by topoisomerases
additional information
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the enzyme-DNA covalent adduct is recombinogenic in cells, because the nicked strand downstream of the cleavage site can dissociate and be replaced by another DNA strand, potentially resulting in genome rearrangements if the enzyme executes strand ligation. The enzyme plays an active role in strand exchange, either by altering the kinetics or thermodynamics of DNA strand binding, or by serving as a proofreading gate to prevent ligation of incoming DNA strands containing mismatches. Topo I-mediated strand exchange can be divided into two distinct steps: (1) a strand binding step, which involves replacement of the nicked, base paired DNA strand with a new incoming strand, and (2) a strand ligation step, which results in covalent attachment of the new DNA strand at the vTopo cleavage site. Oscillation between an open and closed state of the covalently bound enzyme is likely important for regulating the number of DNA superhelical turns that are removed during the lifetime of the covalent complex with supercoiled substrates. vTopo also resolves pre-formed Holliday junctions that contain the consensus cleavage sequence, and when recombinantly expressed in Escherichia coli, promotes illegitimate recombination
additional information
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the TOPRIM motif DxDxxG is strictly conserved in type IA topoisomerase sequences and plays an essential role for divalent ion coordination and cleavage-religation of DNA during catalysis
additional information
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induction of mutant YpTOP1-D117N topoisomerase I in Escherichia coli strain BW117N with 0.002%-0.02% arabinose results in a 104-105fold decrease in viability due to the lethal stabilized covalent complex
additional information
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residues L617, R621, and E710 are important for the functionality of the linker in the enzyme
additional information
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residues R169, R173 and Y177 work together to interact with a cytosine base at the -4 position to facilitate DNA cleavage. R169 and R173 interact with the cytosine base at the -4 position via hydrogen bonds while the phenol ring of Y177 wedges between the bases at the -4 and the -5 position
additional information
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structure-function-relationship, overview. Topo I is one of several protein kinases that phosphorylate SR proteins, enzymes of both families, SRPK1 and CLK1. SRPK1 efficiently phosphorylates serine residues localized in the N-terminal fragment of RS in SRSF1,23,24 while CLK1 phosphorylates all serine residues in RS25 or serine residues in the C-terminal portion of RS in SRSF1 previously phosphorylated by SRPK1. Topoisomerase I interacts with kinase SRSF1, interaction analysis with wild-type and mutant Topo I and wild-type and mutant SrSF1 kinase, phosphorylation sites, modeling, overview. Interactions between N-terminal domain and other domains of topo I are different for the protein in a complex with either DNA or SRSF1
additional information
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the C-terminal domain contains three basic stretches that are essential for the DNA relaxation activity. The basic amino acid stretches confer the non-specific DNA-binding property to the C-terminal domain, overview
additional information
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TopA contains an N-terminal catalytic fragment and a C-terminal zinc-binding region that is required for relaxation of the negatively supercoiled DNA
additional information
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YrdD is a homologue of the C-terminal zinc binding region of Escherichia coli topoisomerase I. The enzyme contains an N-terminal catalytic fragment and a C-terminal zinc binding region. While the N-terminal fragment is sufficient for cleaving single-stranded DNA, the C-terminal region is required for relaxing the negatively supercoiled DNA and for interacting with RNA polymerase
additional information
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LdTopIIIbeta suppresses the yeast top3DELTA slow-growth phenotype. The C-terminal domain of LdTopIIIbeta is essential for in vivo complementation
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additional information
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induction of mutant YpTOP1-D117N topoisomerase I in Escherichia coli strain BW117N with 0.002%-0.02% arabinose results in a 104-105fold decrease in viability due to the lethal stabilized covalent complex
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