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)

Sgs1, the RecQ helicase homolog, and Top3, the type-IA topoisomerase, physically interact and are required for genomic stability in budding yeast. Similarly, topoisomerase III genes physically pair with homologs of SGS1 in humans that are involved in the cancer predisposition and premature aging diseases Bloom, Werner, and Rothmund-Thompson syndromes. In the absence of Top1 activity, sgs1 mutants are severely growth impaired. Here, we investigate the role of Sgs1 helicase activity and its N-terminal Top3 interaction domain by using an allele-replacement technique to integrate mutant alleles at the native SGS1 genomic locus. We compare the phenotype of helicase-defective (sgs1-hd) and N-terminal deletion (sgs1-NDelta) strains to wild-type and sgs1 null strains. Like the sgs1 null, sgs1-hd mutations suppress top3 slow growth, cause a growth defect in the absence of Srs2 helicase, and impair meiosis. However, for recombination and the synthetic interaction with top1Delta mutations, loss of helicase activity exhibits a less severe phenotype than the null. Interestingly, deletion of the Top3 interaction domain of Sgs1 causes a top3-like phenotype, and furthermore, this effect is dependent on helicase activity. These results suggest that the protein-protein interaction between these two DNA-metabolism enzymes, even in the absence of helicase activity, is important for their function in catalyzing specific changes in DNA topology.
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PMID:The genetic consequences of ablating helicase activity and the Top3 interaction domain of Sgs1. 1827 35

The BLAP75 protein combines with the BLM helicase and topoisomerase (Topo) IIIalpha to form an evolutionarily conserved complex, termed the BTB complex, that functions to regulate homologous recombination. BLAP75 binds DNA, associates with both BLM and Topo IIIalpha, and enhances the ability of the BLM-Topo IIIalpha pair to branch migrate the Holliday junction (HJ) or dissolve the double Holliday junction (dHJ) structure to yield non-crossover recombinants. Here we seek to understand the relevance of the biochemical attributes of BLAP75 in HJ processing. With the use of a series of BLAP75 protein fragments, we show that the evolutionarily conserved N-terminal third of BLAP75 mediates complex formation with BLM and Topo IIIalpha and that the DNA binding activity resides in the C-terminal third of this novel protein. Interestingly, the N-terminal third of BLAP75 is just as adept as the full-length protein in the promotion of dHJ dissolution and HJ unwinding by BLM-Topo IIIalpha. Thus, the BLAP75 DNA binding activity is dispensable for the ability of the BTB complex to process the HJ in vitro. Lastly, we show that a BLAP75 point mutant (K166A), defective in Topo IIIalpha interaction, is unable to promote dHJ dissolution and HJ unwinding by BLM-Topo IIIalpha. This result provides proof that the functional integrity of the BTB complex is contingent upon the interaction of BLAP75 with Topo IIIalpha.
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PMID:Functional role of BLAP75 in BLM-topoisomerase IIIalpha-dependent holliday junction processing. 1839 May 47

Bloom's syndrome is caused by mutations in the BLM gene. The BLM gene product, BLM helicase, forms a complex with two other proteins, DNA topoisomerase IIIalpha and RMI1. In this issue of Genes & Development, Wang and colleagues (2843-2855) and Meetei and colleagues (2856-2868) report the discovery of a fourth component of this complex called RMI2. RMI2 may be a representative of a new family of OB-fold-containing proteins that are important for complex stabilization and checkpoint response.
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PMID:More complexity to the Bloom's syndrome complex. 1892 83

BLM, the helicase mutated in Bloom syndrome, associates with topoisomerase 3alpha, RMI1 (RecQ-mediated genome instability), and RPA, to form a complex essential for the maintenance of genome stability. Here we report a novel component of the BLM complex, RMI2, which interacts with RMI1 through two oligonucleotide-binding (OB)-fold domains similar to those in RPA. The resulting complex, named RMI, differs from RPA in that it lacks obvious DNA-binding activity. Nevertheless, RMI stimulates the dissolution of a homologous recombination intermediate in vitro and is essential for the stability, localization, and function of the BLM complex in vivo. Notably, inactivation of RMI2 in chicken DT40 cells results in an increased level of sister chromatid exchange (SCE)--the hallmark feature of Bloom syndrome cells. Epistasis analysis revealed that RMI2 and BLM suppress SCE within the same pathway. A point mutation in the OB domain of RMI2 disrupts the association between BLM and the rest of the complex, and abrogates the ability of RMI2 to suppress elevated SCE. Our data suggest that multi-OB-fold complexes mediate two modes of BLM action: via RPA-mediated protein-DNA interaction, and via RMI-mediated protein-protein interactions.
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PMID:RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. 1892 71

The BLM helicase associates with the telomere structural proteins TRF1 and TRF2 in immortalized cells using the alternative lengthening of telomere (ALT) pathways. This work focuses on identifying protein partners of BLM in cells using ALT. Mass spectrometry and immunoprecipitation techniques have identified three proteins that bind directly to BLM and TRF2 in ALT cells: telomerase-associated protein 1 (TEP1), heat shock protein 90 (HSP90), and topoisomerase IIalpha (TOPOIIalpha). BLM predominantly co-localizes with these proteins in foci actively synthesizing DNA during late S and G(2)/M phases of the cell cycle when ALT is thought to occur. Immunoprecipitation studies also indicate that only HSP90 and TOPOIIalpha are components of a specific complex containing BLM, TRF1, and TRF2 but that this complex does not include TEP1. TEP1, TOPOIIalpha, and HSP90 interact directly with BLM in vitro and modulate its helicase activity on telomere-like DNA substrates but not on non-telomeric substrates. Initial studies suggest that knockdown of BLM in ALT cells reduces average telomere length but does not do so in cells using telomerase.
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PMID:Telomerase-associated protein 1, HSP90, and topoisomerase IIalpha associate directly with the BLM helicase in immortalized cells using ALT and modulate its helicase activity using telomeric DNA substrates. 1932 95

DNA strand passage through an enzyme-mediated gate is a key step in the catalytic cycle of topoisomerases to produce topological transformations in DNA. In most of the reactions catalyzed by topoisomerases, strand passage is not directional; thus, the enzyme simply provides a transient DNA gate through which DNA transport is allowed and thereby resolves the topological entanglement. When studied in isolation, the type IA topoisomerase family appears to conform to this rule. Interestingly, type IA enzymes can carry out directional strand transport as well. We examined here the biochemical mechanism for directional strand passage of two type IA topoisomerases: reverse gyrase and a protein complex of topoisomerase III alpha and Bloom helicase. These enzymes are able to generate vectorial strand transport independent of the supercoiling energy stored in the DNA molecule. Reverse gyrase is able to anneal single strands, thereby increasing linkage number of a DNA molecule. However, topoisomerase III alpha and Bloom helicase can dissolve DNA conjoined with a double Holliday junction, thus reducing DNA linkage. We propose here that the helicase or helicase-like component plays a determinant role in the directionality of strand transport. There is thus a common biochemical ground for the directional strand passage for the type IA topoisomerases.
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PMID:Helicase-appended topoisomerases: new insight into the mechanism of directional strand transfer. 1972 68

Fanconi Anemia (FA) and Bloom's Syndrome (BS) are genetic disorders characterized by overlapping phenotypes, including aberrant DNA repair and cancer predisposition. Here, we show that the FANCM gene product, FANCM protein, links FA and BS by acting as a protein anchor and bridge that targets key components of the FA and BS pathways to stalled replication forks, thus linking multiple components that are necessary for efficient DNA repair. Two highly conserved protein:protein interaction motifs in FANCM, designated MM1 and MM2, were identified. MM1 interacts with the FA core complex by binding to FANCF, whereas MM2 interacts with RM1 and topoisomerase IIIalpha, components of the BS complex. The MM1 and MM2 motifs were independently required to activate the FA and BS pathways. Moreover, a common phenotype of BS and FA cells-an elevated frequency of sister chromatid exchanges-was due to a loss of interaction of the two complexes through FANCM.
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PMID:FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. 2006 55

In eukaryotes, homologous recombination (HR) provides an important means to eliminate DNA double-stranded breaks and other chromosomal lesions. Accordingly, failure in HR leads to genomic instability and a predisposition to various cancer types. While HR is clearly beneficial for genome maintenance, inappropriate or untimely events can be harmful. For this reason, HR must be tightly regulated. Several DNA helicases contribute to HR regulation, by way of mechanisms that are conserved from yeast to humans. Mutations in several HR-specific helicases e.g. BLM and RECQ5, are either associated with cancer-prone human syndromes or engender the cancer phenotype in animal models. Therefore, delineating the role of DNA helicases in HR regulation has direct relevance to cancer etiology. Genetic, cytological, biochemical, and other analyses have shown that DNA helicases participate in early or late stages of HR, to disrupt nucleoprotein filaments that harbor the Rad51 recombinase or dissociate the D-loop intermediate made by Rad51, or to prevent undesirable events and/or minimize potentially deleterious crossover products. Moreover, the ensemble that harbors BLM and topoisomerase IIIalpha can dissolve the double-Holliday junction, a complex DNA intermediate generated during HR, to produce non-crossover products. These regulatory pathways function in parallel to promote the usage of the genome-preserving synthesis-dependent strand annealing HR pathway or otherwise suppress crossover formation.
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PMID:Promotion and regulation of homologous recombination by DNA helicases. 2015 60

Human topoisomerase IIIalpha is a type IA DNA topoisomerase that functions with BLM and RMI1 to resolve DNA replication and recombination intermediates. BLM, human topoisomerase IIIalpha, and RMI1 catalyze the dissolution of double Holliday junctions into noncrossover products via a strand-passage mechanism. We generated single-stranded catenanes that resemble the proposed dissolution intermediate recognized by human topoisomerase IIIalpha. We demonstrate that human topoisomerase IIIalpha is a single-stranded DNA decatenase that is specifically stimulated by the BLM-RMI1 pair. In addition, RMI1 interacts with human topoisomerase IIIalpha, and the interaction is required for the stimulatory effect of RMI1 on decatenase activity. Our data provide direct evidence that human topoisomerase IIIalpha functions as a decatenase with the assistance of BLM and RMI1 to facilitate the processing of homologous recombination intermediates without crossing over as a mechanism to preserve genome integrity.
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PMID:Human topoisomerase IIIalpha is a single-stranded DNA decatenase that is stimulated by BLM and RMI1. 2044 7

All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure-specific "dissolvasome," also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans, the heteromeric RTR complex consists of RMI1, RMI2, the Bloom's syndrome gene product (BLM), and topoisomerase 3A (TOP3A) proteins. Here, we describe the identification and characterization of two deleterious mutations in the zebrafish top3a gene that reveal an unexpected tissue-specific requirement of top3a function in developing thymocytes. Deficiency in top3a activates a p53-dependent check-point but does not affect VDJ recombination. Our results suggest that TOP3A could be a candidate gene involved in human primary immunodeficiency syndromes.
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PMID:Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha. 2062 52


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