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evolution
conservation of the active site motifs typical for all Tdp1 proteins
evolution
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs
evolution
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs
evolution
E2REL5
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs
evolution
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs
evolution
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs
evolution
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs, three-dimensional structural comparison of four PLD superfamily members, overview
evolution
the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs, three-dimensional structural comparison of PLD superfamily members, overview
evolution
the enzyme is a member of the metallophosphoesterase enzyme family, the molecular mass of secreted SMPDL3A is tissue and/or species dependent
evolution
the enzyme is a member of the metallophosphoesterase enzyme family, the molecular mass of secreted SMPDL3A is tissue and/or species dependent
evolution
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the enzyme is a member of the phospholipase D superfamily of enzymes that catalyze the hydrolysis of a variety of phosphodiester bonds in many different substrates
evolution
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the enzyme is phylogenetically conserved
evolution
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the enzymes belongs to the ectonucleotide pyrophosphatase/phosphodiesterase (NPP) family
evolution
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tyrosyl-DNA phosphodiesterase I is a member of the phospholipase D superfamily of enzymes
evolution
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the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs, three-dimensional structural comparison of PLD superfamily members, overview
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evolution
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the enzyme is a member of the metallophosphoesterase enzyme family, the molecular mass of secreted SMPDL3A is tissue and/or species dependent
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malfunction
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PC-1 is the major source of the elevated phosphate levels in chondrocytes and fibroblasts of patients with familial calcium pyrophosphate dehydrate deposition disease, CPPD. CPPD crystals may be a hallmark of the pathology of osteoarthritis
malfunction
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Pde1c-/- and Pde4a-/- knockout mutants to examine the role of the PDEs in olfactory transduction. Pde1c-/- OSNs (olfactory sensory neuron cilia) show reduced sensitivity and attenuated adaptation to repeated stimulation, suggesting that PDE1C may be involved in regulating sensitivity and adaptation
malfunction
a loss-of-function AtTDP mutation displays developmental defects and dwarf phenotype in Arabidopsis. This phenotype is substantially caused by decreased cell numbers without any change of individual cell sizes. The tdp plants exhibit hypersensitivities to camptothecin, a potent topoisomerase I inhibitor, and show rigorous cell death in cotyledons and rosette leaves, suggesting the failure of DNA damage repair in tdp mutants
malfunction
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mutations of the Tdp1 gene are involved in the disease spinocerebellar ataxia with axonal neuropathy
malfunction
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phosphodiesterase-1 inhibition decreases vascular contraction in arteries from angiotensin II hypertensive, but not control, rats
malfunction
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aberrant nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is associated with chondrocalcinosis, osteoarthritis, and type 2 diabetes
malfunction
deletion of the enzyme in budding yeast leads to an increase in Topo1-dependent cytotoxicity either induced by expression of the toxic Topo1T722A mutant enzyme or cells treated with camptothecin
malfunction
Tdp1-/- enzyme knockout mice do not show increased sensitivity to etoposide, i.e. VP16
malfunction
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Tdp1-knock-out Gallus gallus DT40 cells are hypersensitive to camptothecin and bleomycin but also to etoposide, methyl methanesulfonate, H2O2, and ionizing radiation and they are deficient in mitochondrial enzyme activity, phenotype, overview
malfunction
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the c03958 insertion gene gkt disruption mutant of TDP1 is generally healthy and fertile, but females exhibit reduced lifespan and diminished climbing ability. Insertion mutant c03958 larvae are exposed to bleomycin, an agent that produces oxidative DNA damage, or topoisomerase I-targeted drugs (camptothecin and a noncamptothecin indenoisoquinoline derivative, LMP-776), survivors display rough eye patches, which are rescued by neuronal expression of wild-type enzyme TDP1, overview
malfunction
the mutation H493R forms the molecular basis for the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy, SCAN1, and results in an increased stability of its Tdp1-DNA reaction intermediate, overview. Enzyme inhibition might potentiate camptothecin-based chemotherapy, overview
malfunction
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whilst the enzyme mutants H493R (SCAN1) and H263A retain the ability to bind an apurinic/apyrimidinic site-containing DNA, both mutants do not reveal endonuclease activity
malfunction
enzyme knockdown cells are hypersensitive to etoposide. Late, but not early double-stranded break signaling response is altered in human cells lacking the enzyme. Enzyme knockdown impairs the repair of topoisomerase II-induced DNA double-stranded breaks
malfunction
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deletion of the enzyme in budding yeast leads to an increase in Topo1-dependent cytotoxicity either induced by expression of the toxic Topo1T722A mutant enzyme or cells treated with camptothecin
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metabolism
(R,S)-isoproterenol decreases the amount of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 protein by 75% and 81%, respectively. Contrary to downregulation of ecto-nucleotide pyrophosphatase/phosphodiesterase 1, an upregulation of glial fibrillary acidic protein, a differentiation marker for astrocytic cells is observed. Ca2+, PKA, PI 3-K/PKB/GSK-3, Epac/Rap1/PP2A and MAP kinase modules are not involved in the inhibition of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene expression, overview
metabolism
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TDP1 knockdown does not produce a change in sensitivity to camptothecin, whereas co-silencing of other pathways cooperating with TDP1 in cell response to topoisomerase I poisons indicates that XRCC1 and BRCA1 are major regulators of sensitivity
metabolism
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the tyrosyl-DNA phosphodiesterase I hydrolyzes the phosphotyrosyl linkage between degraded Top1 and DNA, then polynucleotide kinase phosphatase hydrolyzes the resulting 3'-phosphate end and catalyzes the phosphorylation of the 5'-hydroxyl end of the broken DNA strand. This results in a broken DNA strand with termini consisting of a 5'-phosphate and 3'-hydroxyl for DNA repair. DNA polymerase beta replaces the missing DNA segment, and finally DNA ligase III reseals the broken DNA. Tyrosyl-DNA phosphodiesterase I is the only enzyme that specifically catalyzes the hydrolysis of the phosphodiester bond between the catalytic Tyr723 of Top1 and DNA-3'-phosphate
metabolism
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(R,S)-isoproterenol decreases the amount of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 protein by 75% and 81%, respectively. Contrary to downregulation of ecto-nucleotide pyrophosphatase/phosphodiesterase 1, an upregulation of glial fibrillary acidic protein, a differentiation marker for astrocytic cells is observed. Ca2+, PKA, PI 3-K/PKB/GSK-3, Epac/Rap1/PP2A and MAP kinase modules are not involved in the inhibition of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene expression, overview
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physiological function
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PC-1 is an enzymatic generator of diphosphate and a critical regulator of tissue mineralization
physiological function
AtTDP plays a clear role in the repair of topoisomerase I-DNA complexes in Arabidopsis, the tyrosyl-DNA phosphodiesterase 1 is a key enzyme that hydrolyzes the phosphodiester bond between tyrosine of topoisomerase and 3'-phosphate of DNA and repairs topoisomerase-mediated DNA damage during chromosome metabolism. Recombinant AtTDP protein certainly hydrolyzes the 3'-phosphotyrosyl DNA substrates related to repairing in vivo topoisomerase I-DNA-induced damage
physiological function
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phosphodiesterase 1 plays a role in decreased cGMP level contributing to increased contraction in arteries from hypertensive rats. Ang II augments PDE1 activation, decreasing the bioavailability of cyclic guanosine 3',5'-monophosphate, and contributing to increased vascular contractility, effects of different PDF isozymes, overview
physiological function
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role and underlying mechanism of cyclic nucleotide phosphodiesterase 1, PDE1, in regulating collagen I in synthetic vascular smooth muscle cells, overview
physiological function
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role of Tdp1 in the new APE-independent base excision repair pathway in mammals
physiological function
th enzyme participates in topoisomerase I-mediated DNA damage repair process and thereby counteracts the cytotoxic effect of topoisomerase I inhibitors
physiological function
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tyrosyl-DNA phosphodiesterase 1 catalyses the hydrolysis of phosphodiester linkages between a DNA 3' phosphate and a tyrosine residue as well as a variety of other DNA 3 substituents, and is implicated in the repair of covalent complexes involving eukaryotic type IB topoisomerases. Processing by the proteasome is required for TDP1 cleavage in vivo
physiological function
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tyrosyl-DNA phosphodiesterase 1 is a key enzyme that hydrolyzes the phosphodiester bond between tyrosine of topoisomerase and 3'-phosphate of DNA and repairs topoisomerase-mediated DNA damage during chromosome metabolism
physiological function
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tyrosyl-DNA phosphodiesterase 1 is an enzyme vital to the repair of covalent DNA-topoisomerase adducts, e.g. induced by the mycotoxin alternariol, it affects alternariol-mediated genotoxicity. TDP1 plays an important role in the repair of topoisomerase-mediated DNA damage. The repair enzyme TDP1 is a factor for the modulation of AOH-mediated DNA damage in human cells. TDP1 is also involved in the repair of topoisomerase II-induced DNA damage
physiological function
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tyrosyl-DNA phosphodiesterase 1 plays a unique function as it catalyzes the repair of topoisomerase I-mediated DNA damage. TDP1 alone can account for mild levels of camptothecin resistance, repair of topoisomerase I-mediated DNA damage likely occurs through redundant pathways mainly implicating BRCA1 and XRCC1, but not RAD17 and PARP1
physiological function
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human tyrosyl-DNA phosphodiesterase 1 catalyzes the apurinic/apyrimidinic site cleavage reaction to generate breaks with the 3'- and 5'-phosphate termini. The enzyme activity can contribute to the repair of apurinic/apyrimidinic sites particularly in DNA structures containing ssDNA region or apurinic/apyrimidinic sites in the context of clustered DNA lesions
physiological function
SMPDL3A is the major nucleotide phosphodiesterase secreted by human THP-1 macrophages after LXR stimulation, it may play a novel role in the pathobiology of atherosclerosis. SMPDL3A is a major source of nucleotide phosphodiesterase activity secreted by LXR-stimulated human macrophages, enzyme expression and secretion is regulated by intracellular cAMP, and is regulated by liver X receptor, LXR,. The CREs in the promoter region of SMPDL3A may play a functional role in primary human macrophages. The enzyme is capable of hydrolyzing sphingomyelin in oxidized LDL particles, transforming them into a more aggregation prone form which is more readily retained by arterial proteoglycans. But SMPDL3A is not an acid sphingomyelinase, but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH
physiological function
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the enzyme is critical for neuroprotection, normal longevity, and repair of damaged DNA through the removal of blocking lesions at the 3'-ends of DNA or RNA
physiological function
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the enzyme plays a critical role in the cellular repair of topoisomerase 1-mediated DNA damage
physiological function
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the enzyme plays a key role in the repair of damaged DNA resulting from the topoisomerase I inhibitor camptothecin and a variety of other DNA-damaging anticancer agents
physiological function
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tyrosyl-DNA phosphodiesterase 1 repairs topoisomerase I cleavage complexes by hydrolyzing their 3'-phosphotyrosyl DNA bonds and repairs bleomycin-induced DNA damage by hydrolyzing 3'-phosphoglycolates
physiological function
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tyrosyl-DNA phosphodiesterase 1 repairs topoisomerase I cleavage complexes by hydrolyzing their 3'-phosphotyrosyl DNA bonds and repairs bleomycin-induced DNA damage by hydrolyzing 3'-phosphoglycolates. The yeast enzyme is also implicated in the repair of topoisomerase II-DNA cleavage complexes. The enzyme and CtIP act in parallel pathways for the repair of topoisomerase I cleavage complexes and methyl methanesulfonate-induced lesions but are epistatic for topoisomerase II cleavage complexes
physiological function
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA
physiological function
E2REL5
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA
physiological function
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA
physiological function
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA
physiological function
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. Phosphorylation of Ser81 regulates hTdp1 targeting to sites of DNA damage and stabilizes its interaction with X-ray repair cross-complementing protein 1 (XRCC1) and/or DNA ligase III similar to how ATM-mediated phosphorylation of PNKP promotes its activity at DNA lesions. The human enzyme expressed in DT40 chicken B-lymphoblast cells plays a protective role against etoposide
physiological function
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. The enzyme may play a role in chemo-resistance to pharmacologic inhibitors of topoisomerase I
physiological function
tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. The enzyme plays a role in suppressing etoposide-induced DNA damage
physiological function
the enzyme catalyzes the repair of 3'-DNA adducts, such as the 3'-phosphotyrosyl linkage of DNA topoisomerase I to DNA
physiological function
the enzyme plays a key role in the removal of DNA damage resulting from Topo1 inhibition or caused by other anticancer drugs, e.g., temozolomide, bleomycin, etoposide, etc.
physiological function
tyrosyl-DNA-phosphodiesterase 1 is a DNA repair enzyme that removes irreversible protein-linked 3'-DNA complexes, 3'-phosphoglycolates, alkylation damage-induced DNA breaks, and 3'-deoxyribose nucleosides. The enzyme plays an active role in the repair of topoisomerase II-induced DNA damage
physiological function
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phosphodiesterase 1 plays a role in decreased cGMP level contributing to increased contraction in arteries from hypertensive rats. Ang II augments PDE1 activation, decreasing the bioavailability of cyclic guanosine 3',5'-monophosphate, and contributing to increased vascular contractility, effects of different PDF isozymes, overview
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physiological function
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tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. The enzyme may play a role in chemo-resistance to pharmacologic inhibitors of topoisomerase I
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additional information
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knockdown of the enzyme TDP1 in U2-OS cells does not increase sensitivity to gimatecan
additional information
overexpression of the active enzyme protects the parasites against topoisomerase IB inhibitor camptothecin and oxidative agent H2O2-mediated cytotoxicity and its downregulation rendered the parasites hypersensitive to camptothecin. Downregulation of LdTdp1 mRNA occurs because of blockage of transcription rather than increased turnover, transcriptional regulation, overview
additional information
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overexpression of the active enzyme protects the parasites against topoisomerase IB inhibitor camptothecin and oxidative agent H2O2-mediated cytotoxicity and its downregulation rendered the parasites hypersensitive to camptothecin. Downregulation of LdTdp1 mRNA occurs because of blockage of transcription rather than increased turnover, transcriptional regulation, overview
additional information
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Tdp1 is known to interact stably with BER proteins: DNA polymerase beta, XRCC1, PARP1 and DNA ligase III
additional information
expression and sequence comparisons, overview
additional information
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expression and sequence comparisons, overview
additional information
expression and sequence comparisons, overview
additional information
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the enzyme is composed of two domains related by a pseudo-twofold axis of symmetry. Each domain contributes a histidine and a lysine residue to form an active site that is centrally located at the symmetry axis. Four additional residues N283, Q294, N516, and E538 are also positioned near the active site
additional information
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expression and sequence comparisons, overview
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