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 mechanism of chromosome condensation is one of the classic mysteries of mitosis. A number of years ago, it was suggested that nonhistone proteins of the chromosome scaffold fraction might help chromosomes to condense, possibly by constructing a framework for the condensed structure. Recent results have shown that topoisomerase II and the SMC proteins, two abundant members of the scaffold fraction, are required for chromosome condensation and segregation during mitosis. Topoisomerase II is a well-characterized enzyme. In contrast, nothing is yet known about the function of the SMC proteins. We summarize evidence suggesting that these proteins may be enzymes whose activity is somehow involved in the establishment and maintenance of mitotic chromosome morphology.
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PMID:The SMC proteins and the coming of age of the chromosome scaffold hypothesis. 876 28

In this chapter, we review the structure and composition of interphase and mitotic chromosomes. We discuss how these observations support the model that mitotic condensation is a deterministic process leading to the invariant folding of a given chromosome. The structural studies have also placed constraints on the mechanism of condensation and defined several activities needed to mediate condensation. In the context of these activities and structural information, we present our current understanding of the role of cis sites, histones, topoisomerase II, and SMC proteins in condensation. We conclude by using our current knowledge of mitotic condensation to address the differences in chromosome condensation observed from bacteria to humans and to explore the relevance of this process to other processes such as gene expression.
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PMID:Mitotic chromosome condensation. 897 Jul 29

We report here purification and characterization of chromosome condensation protein complexes (termed condensins) containing XCAP-C and XCAP-E, two Xenopus members of the SMC family. Sucrose density gradient centrifugation reveals two major forms of condensins. The 8S form is a heterodimer of XCAP-C and XCAP-E, whereas the 13S form contains three additional subunits. One of them is identified as a homolog of the Drosophila Barren protein whose mutation shows a defect in chromosome segregation. Chromosomal targeting of condensins is mitosis-specific and is independent of topoisomerase IIalpha. 13S condensin is required for condensation, as demonstrated by immunodepletion and rescue experiments. Our results suggest that the condensin complexes represent the most abundant structural components of mitotic chromosomes and play a central role in driving chromosome condensation.
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PMID:Condensins, chromosome condensation protein complexes containing XCAP-C, XCAP-E and a Xenopus homolog of the Drosophila Barren protein. 916 Jul 43

Chromosome condensation occurs in mitosis before the separation of sister chromatids, and requires DNA topoisomerase II and a group of proteins called SMCs. The resulting condensed chromosomes in metaphase have a complex hierarchical structure. SMCs, the components of condensed chromosomes, are also required for the separation of sister chromatids and gene dosage compensation, and are found in a range of organisms from yeasts to mammals. However, the mechanisms by which the SMCs contribute to chromosome condensation are unknown. We have studied chromosomes in fission-yeast SMC mutants cut3-477 and cut14-208, which remain largely non-condensed during mitosis at the restrictive temperature (36 degrees C). To test their role in DNA condensation, we isolated the proteins Cut3 and Cut14 as an oligomeric complex, and tested their interactions with isolated DNA. The complex efficiently promoted the DNA renaturation reactions (the winding up of single-strand DNAs into double helical DNA) as much as approximately 70-fold more efficiently than RecA, which is a bacterial protein with similar activity. The activity of the mutant complex was heat sensitive. As DNA winding by renaturation is a potential cause of supercoiling, the SMC complex may be implicated in promoting the higher-order DNA coiling found in condensed chromosomes.
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PMID:DNA renaturation activity of the SMC complex implicated in chromosome condensation. 928 94

Topoisomerases maintain DNA structure by relieving torsional stress occurring in DNA during transcription, replication and cell division. Topoisomerases are of two main types, causing transient breaks in one (type I) or both (type II) and strands of DNA, and a number of clinical anticancer drugs are thought to act by inhibiting religation of these transient breaks. Topoisomerase II appears to have a close association with the SMC (stable maintenance of chromosomes) family of proteins involved in organisation of the chromatin in a series of loops on the proteinaceous chromosomal scaffold. Inhibition of topoisomerase II function can result in deletions of such loops, probably mediated by reciprocal exchange of topoisomerase subunits. Disruption of topoisomerase I and/or II function during DNA replication results in smaller DNA deletions and other mutations, probably arising from non-homologous recombination. Inhibition of topoisomerase II action during mitosis and meiosis can cause incomplete separation of chromatids and chromosomes, with the consequent production of genomic mutations. Topoisomerase-mediated mutagenicity is important because it can lead not only to drug resistance but also to drug-induced secondary cancers. Mutagenicity of topoisomerase-directed agents has been underestimated in the past, since these drugs are not usually capable of reacting covalently with DNA and usually have low mutagenicity in microbial assays.
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PMID:Mutagenic properties of topoisomerase-targeted drugs. 974 84

The establishment of sister chromatid cohesion during S phase and its dissolution at the metaphase-anaphase transition are essential for the faithful segregation of chromosomes in mitosis [1-4]. Recent studies in yeast genetics and Xenopus biochemistry have identified a large protein complex, cohesin, that plays a key role in sister chromatid cohesion [5-10]. The cohesin complex consists of a heterodimeric pair of SMC (structural maintenance of chromosomes) subunits and at least two non-SMC subunits. This structural organization is reminiscent of that of condensin, another major SMC protein complex that drives chromosome condensation in eukaryotic cells [11]. Condensin has been shown to reconfigure and compact DNA in vitro by utilizing the energy of ATP hydrolysis [12]. Very little is known, however, about how cohesin works at a mechanistic level. Here we report the first set of biochemical activities associated with an intact cohesin complex purified from HeLa cell extracts. The cohesin complex binds directly to double-stranded DNA and induces the formation of large protein-DNA aggregates. In the presence of topoisomerase II, cohesin stimulates intermolecular catenation of circular DNA molecules. This activity is in striking contrast to intramolecular knotting directed by condensin [13]. Cohesin also increases the probability of intermolecular ligation of linear DNA molecules in the presence of DNA ligase. Our results are consistent with a model in which cohesin functions as an intermolecular DNA crosslinker and is part of the molecular "glue" that holds sister chromatids together [14].
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PMID:Intermolecular DNA interactions stimulated by the cohesin complex in vitro: implications for sister chromatid cohesion. 1125 Jan 56

Assembly of compact mitotic chromosomes and resolution of sister chromatids are two essential processes for the correct segregation of the genome during mitosis. Condensin, a five-subunit protein complex, is thought to be required for chromosome condensation. However, recent genetic analysis suggests that condensin is only essential to resolve sister chromatids. To study further the function of condensin we have depleted DmSMC4, a subunit of the complex, from Drosophila S2 cells by dsRNA-mediated interference. Cells lacking DmSMC4 assemble short mitotic chromosomes with unresolved sister chromatids where Barren, a non-SMC subunit of the complex is unable to localise. Topoisomerase II, however, binds mitotic chromatin after depletion of DmSMC4 but it is no longer confined to a central axial structure and becomes diffusely distributed all over the chromatin. Furthermore, cell extracts from DmSMC4 dsRNA-treated cells show significantly reduced topoisomerase II-dependent DNA decatenation activity in vitro. Nevertheless, DmSMC4-depleted chromosomes have centromeres and kinetochores that are able to segregate, although sister chromatid arms form extensive chromatin bridges during anaphase. These chromatin bridges do not result from inappropriate maintenance of sister chromatid cohesion by DRAD21, a subunit of the cohesin complex. Moreover, depletion of DmSMC4 prevents premature sister chromatid separation, caused by removal of DRAD21, allowing cells to exit mitosis with chromatin bridges. Our results suggest that condensin is required so that an axial chromatid structure can be organised where topoisomerase II can effectively promote sister chromatid resolution.
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PMID:Condensin-dependent localisation of topoisomerase II to an axial chromosomal structure is required for sister chromatid resolution during mitosis. 1460 Feb 62

Eukaryotic chromosomes undergo dramatic changes and movements during mitosis. These include the individualization and compaction of the two copies of replicated chromosomes (the sister chromatids) and their subsequent segregation to the daughter cells. Two multisubunit protein complexes termed 'cohesin' and 'condensin', both composed of SMC (Structural Maintenance of Chromosomes) and kleisin subunits, have emerged as crucial players in these processes. Cohesin is required for holding sister chromatids together whereas condensin, together with topoisomerase II, has an important role in organizing individual axes of sister chromatids prior to their segregation during anaphase. SMC and kleisin complexes also regulate the compaction and segregation of bacterial nucleoids. New research suggests that these ancient regulators of chromosome structure might function as topological devices that trap chromosomal DNA between 50 nm long coiled coils.
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PMID:Building and breaking bridges between sister chromatids. 1463 53

Condensins are heteropentameric complexes that were first identified as structural components of mitotic chromosomes. They are composed of two SMC (structural maintenance of chromosomes) and three non-SMC subunits. Condensins play a role in the resolution and segregation of sister chromatids during mitosis, as well as in some aspects of mitotic chromosome assembly. Two distinct condensin complexes, condensin I and condensin II, which differ only in their non-SMC subunits, exist. Here, we used an RNA interference approach to deplete hCAP-D2, a non-SMC subunit of condensin I, in HeLa cells. We found that the association of hCAP-H, another non-SMC subunit of condensin I, with mitotic chromosomes depends on the presence of hCAP-D2. Moreover, chromatid axes, as defined by topoisomerase II and hCAP-E localization, are disorganized in the absence of hCAP-D2, and the resolution and segregation of sister chromatids are impaired. In addition, hCAP-D2 depletion affects chromosome alignment in metaphase and delays entry into anaphase. This suggests that condensin I is involved in the correct attachment between chromosome kinetochores and microtubules of the mitotic spindle. These results are discussed relative to the effects of depleting both condensin complexes.
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PMID:Contribution of hCAP-D2, a non-SMC subunit of condensin I, to chromosome and chromosomal protein dynamics during mitosis. 1563 74

We now have firm evidence that the basic mechanism of chromosome segregation is similar among diverse eukaryotes as the same genes are employed. Even in prokaryotes, the very basic feature of chromosome segregation has similarities to that of eukaryotes. Many aspects of chromosome segregation are closely related to a cell cycle control that includes stage-specific protein modification and proteolysis. Destruction of mitotic cyclin and securin leads to mitotic exit and separase activation, respectively. Key players in chromosome segregation are SMC-containing cohesin and condensin, DNA topoisomerase II, APC/C ubiquitin ligase, securin-separase complex, aurora passengers, and kinetochore microtubule destabilizers or regulators. In addition, the formation of mitotic kinetochore and spindle apparatus is absolutely essential. The roles of principal players in basic chromosome segregation are discussed: most players have interphase as well as mitotic functions. A view on how the centromere/kinetochore is formed is described.
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PMID:Basic mechanism of eukaryotic chromosome segregation. 1589 83


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