DNA topoisomerase II (topo II) is an essential enzyme that mediates a variety of
chromosome activities including DNA replication, transcription, recombination,
and chromosome condensation and segregation.
Topoisomerase II from eukaryotic cells catalyzes the relaxation of supercoiled DNA
molecules, catenation, decatenation, knotting, and unknotting of circular DNA. It appears likely that the reaction
catalyzed by topoisomerase II involves the crossing-over of 2 DNA segments.
NCBI Summary:
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]
General function
Oncogenesis, Nucleic acid binding, DNA binding
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Cellular localization
Nuclear
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Ovarian function
Oogenesis, Oocyte maturation, Early embryo development
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DNA Topoisomerase II Is Dispensable for Oocyte Meiotic Resumption but Is Essential for Meiotic Chromosome Condensation and Separation in Mice. Li XM 2013 et al.
During mitosis, DNA Topoisomerase II (TOP2) is required for sister chromatid separation. When TOP2 activity is inhibited, a decatenation checkpoint is activated by entangled chromatin. However, the functions of TOP2 in oocyte meiosis, particularly for homologous chromosome segregation during meiosis I, have not been investigated. In addition, it remains unknown if TOP2 inhibition activates a decatenation checkpoint at the G2/M transition in oocytes. In this study, we used mouse oocytes and specific inhibitors of TOP2 (ICRF-193 and VP-16) to investigate the role of TOP2 in meiosis. Our results indicated that an effective decatenation checkpoint did not exist in fully grown oocytes, as oocytes underwent the G2/M transition and reinitiated meiosis even when TOP2 activity was inhibited. However, oocytes treated with ICRF-193 had severe defects in chromosome condensation and homologous chromosome separation. Furthermore, condensed chromosomes failed to maintain their normal configurations in matured oocytes that were treated with ICRF-193. However, sister chromatid separation and subsequent chromosome decondensation during the exit from meiosis were not blocked by TOP2 inhibitors. These results indicated that TOP2 had a specific, crucial function in meiosis I. Thus, we identified important functions of TOP2 during oocyte maturation and provided novel insights into the decatenation checkpoint during meiosis.
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Prior mitotic remodeling of the somatic nuclei, involving
topoisomerase II (TOP2)-dependent shortening of chromatin
loop domains and an increased recruitment of replication
initiation factors onto chromatin, is essential for
reprogramming of differentiated nuclei. Strikingly,
Assou et al 2009 found that TOP2A was highly up-regulated in both
oocytes and hESC. This observation suggests that TOP2A
could be a major factor in the reprogramming properties
of oocytes and hESC by participating in chromatin
remodeling.
A gene expression signature shared by human mature oocytes and embryonic stem cells. Assou S et al. BACKGROUND: The first week of human pre-embryo development is characterized by the induction of totipotency and then pluripotency. The understanding of this delicate process will have far reaching implication for in vitro fertilization and regenerative medicine. Human mature MII oocytes and embryonic stem (ES) cells are both able to achieve the feat of cell reprogramming towards pluripotency, either by somatic cell nuclear transfer or by cell fusion, respectively. Comparison of the transcriptome of these two cell types may highlight genes that are involved in pluripotency initiation. RESULTS: Based on a microarray compendium of 205 samples, we compared the gene expression profile of mature MII oocytes and human ES cells (hESC) to that of somatic tissues. We identified a common oocyte/hESC gene expression profile, which included a strong cell cycle signature, genes associated with pluripotency such as LIN28 and TDGF1, a large chromatin remodelling network (TOP2A, DNMT3B, JARID2, SMARCA5, CBX1, CBX5), 18 different zinc finger transcription factors, including ZNF84, and several still poorly annotated genes such as KLHL7, MRS2, or the Selenophosphate synthetase 1 (SEPHS1). Interestingly, a large set of genes was also found to code for proteins involved in the ubiquitination and proteasome pathway. Upon hESC differentiation into embryoid bodies, the transcription of this pathway declined. In vitro, we observed a selective sensitivity of hESC to the inhibition of the activity of the proteasome. CONCLUSION: These results shed light on the gene networks that are concurrently overexpressed by the two human cell types with somatic cell reprogramming properties.
Expression regulated by
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Ovarian localization
Oocyte
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St Pierre J, et al 2002 reported the DNA topoisomerase II distribution in mouse preimplantation
embryos.
Isoform-specific anti-topo II
antibodies were used to determine the distribution of topo II [alpha] and [beta] in
mouse gametes and embryos. Immunoblot analysis with two anti-topo II[alpha]
antibodies revealed that a 170 kDa topo II[alpha] band was present in ovary and
testis. Mature sperm exhibited an 89 kDa band only, which may be a degradation
product of topo II[alpha]. Immunoblots probed with a monoclonal antibody that
recognizes both isoforms, showed bands at 170 and 180 kDa, which correspond
to topo II[alpha] and [beta], respectively. An additional 100 kDa band was also
present in ovary and testis. Mature sperm did not exhibit staining with this
antibody. While both isoforms
were found in nuclei and nucleoli of germinal vesicle oocytes, topo II[alpha]
localized to metaphase chromosomes during meiosis, and only to nucleoli during
embryonic interphase. Topo II[beta] was absent from chromosomes of metaphase
II oocytes, but localized to embryonic interphase nuclei. Both full-length isoforms
were absent from sperm, indicating topo II is stored maternally. These results
identify topo II as an important component of mouse oocyte and embryonic
chromatin, and suggest its involvement in oocyte maturation and preimplantation
embryonic development. The different immunofluorescent staining patterns
indicate topo II[alpha] and [beta] may serve different roles during the embryonic
cell cycle.
Follicle stages
Secondary, Antral, Preovulatory
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Phenotypes
Mutations
2 mutations
Species: D. melanogaster
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: Topoisomerase II is required for the proper separation of heterochromatic regions during Drosophila melanogaster female meiosis. Hughes SE et al. (2014) Heterochromatic homology ensures the segregation of achiasmate chromosomes during meiosis I in Drosophila melanogaster females, perhaps as a consequence of the heterochromatic threads that connect achiasmate homologs during prometaphase I. Here, we ask how these threads, and other possible heterochromatic entanglements, are resolved prior to anaphase I. We show that the knockdown of Topoisomerase II (Top2) by RNAi in the later stages of meiosis results in a specific defect in the separation of heterochromatic regions after spindle assembly. In Top2 RNAi-expressing oocytes, heterochromatic regions of both achiasmate and chiasmate chromosomes often failed to separate during prometaphase I and metaphase I. Heterochromatic regions were stretched into long, abnormal projections with centromeres localizing near the tips of the projections in some oocytes. Despite these anomalies, we observed bipolar spindles in most Top2 RNAi-expressing oocytes, although the obligately achiasmate 4th chromosomes exhibited a near complete failure to move toward the spindle poles during prometaphase I. Both achiasmate and chiasmate chromosomes displayed defects in biorientation. Given that euchromatic regions separate much earlier in prophase, no defects were expected or observed in the ability of euchromatic regions to separate during late prophase upon knockdown of Top2 at mid-prophase. Finally, embryos from Top2 RNAi-expressing females frequently failed to initiate mitotic divisions. These data suggest both that Topoisomerase II is involved in the resolution of heterochromatic DNA entanglements during meiosis I and that these entanglements must be resolved in order to complete meiosis.//////////////////
Species: C. elegans
Mutation name: type: naturally occurring fertility: None Comment: The Identification of a Novel Mutant Allele of topoisomerase II in Caenorhabditis elegans Reveals a Unique Role in Chromosome Segregation during Spermatogenesis. Jaramillo-Lambert A et al. (2016) Topoisomerase II alleviates DNA entanglements that are generated during mitotic DNA replication, transcription, and sister chromatid separation. In contrast to mitosis, meiosis has two rounds of chromosome segregation following one round of DNA replication. In meiosis II, sister chromatids segregate from each other similar to mitosis. Meiosis I, on the other hand, segregates homologs, which requires pairing, synapsis, and recombination. The exact role that topoisomerase II plays during meiosis is unknown. In a screen re-examining Caenorhabditis elegant legacy mutants isolated thirty years ago, we identified a novel allele of the gene encoding topoisomerase II, top-2(it7) In this study, we demonstrate that top-2(it7) males produce dead embryos, even when fertilizing wild-type oocytes. Characterization of early embryonic events indicates that fertilization is successful and sperm components are transmitted to the embryo. However, sperm chromatin is not detected in these fertilized embryos. Examination of top-2(it7) spermatogenic germ lines reveals that the sperm DNA fails to segregate properly during anaphase I of meiosis resulting in anucleate sperm. top-2(it7) chromosome segregation defects observed during anaphase I are not due to residual entanglements incurred during DNA replication and are not dependent on SPO-11-induced double-strand DNA breaks. Finally, we show that TOP-2 associates with chromosomes in meiotic prophase and that chromosome association is disrupted in the germ lines of top-2(it7) mutants.//////////////////