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, beta, is localized to chromosome 3 and the alpha form is localized to chromosome 17. 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]
General function
Oncogenesis, DNA binding
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Cellular localization
Nuclear
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Ovarian function
Oogenesis
Comment
Advanced maternal age alters expression of maternal effect genes that are essential for human oocyte quality. Zhang JJ et al. (2020) To investigate the effects of maternal age on the quality of oocytes, we used single-cell RNA sequencing to detect global gene transcriptome and identify key genes affected by advanced age in human mature oocytes. We isolated mRNA from mature oocytes obtained from IVF or ICSI patients (three oocytes from younger (≤30 years) and three oocytes from older (≥40 years) patients for scRNA-seq. We identified 357 genes differentially expressed between matured oocytes from older and younger women's. The up-regulated genes were significantly enriched with annotations related to transcriptional activation, oxidative stress and immune function, while down-regulated genes were enriched with catalytic activity. The key candidate gene TOP2B was found by protein interaction network analysis, and knockdown verification on younger mouse matured oocytes showed that TOP2B was a key gene affecting the oocyte quality and early embryo development. These results will contribute new knowledge on the molecular mechanisms of female ovary aging and establish a criterion to evaluate the quality of oocytes in women with advanced maternal age.//////////////////
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
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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
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Yang et al. (2000) disrupted the murine Top2b gene by homologous recombination. Heterozygous mice were
phenotypically indistinguishable from their wildtype littermates, but homozygous Top2b -/- embryos from
intercrosses of the heterozygotes were dead at birth.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: TOP2 Is Essential for Ovarian Follicles That Are Hypersensitive to Chemotherapeutic Drugs. Zhang YL 2013 et al.
The mechanisms underlying chemotherapy-induced acceleration of ovarian insufficiency are not fully understood, particularly for ovarian granulosa cells (GCs). We used two widely used cancer chemotherapeutic reagents, bleomycin and VP-16, and an in vivo GC-specific DNA topoisomerase II- (TOP2) (Top2b) knockout mouse model to investigate the effects of chemotherapy-induced DNA damage on growing mouse follicles. Bleomycin and VP-16 caused massive double-strand DNA breaks in the GCs of growing follicles in a time-dependent manner as shown by DNA-damage checkpoint activation. This damage was associated with apoptotic GC death and resulted in follicle atresia and ovulation failure. However, FSH-regulated ovarian functions, including estrogen biosynthesis and estrogen target gene expression, were not significantly affected by these genotoxins. TOP2, a target of several chemotherapeutic drugs including VP-16, was abundantly expressed in the GCs of growing follicles. GC-specific deletion of Top2b using Cyp19-Cre caused DNA damage accumulations in these cells, follicle atresia, and decreased ovulation in response to exogenous gonadotropins. The ovaries of Top2b conditional knockout mice were also more sensitive to low-dose genotoxin treatment than wild-type mice ovaries. Thus, our results indicate that GCs are hypersensitive to genotoxic chemotherapeutic drugs and can activate the canonical DNA-damage checkpoint and the p53-dependent apoptotic pathway in response to insults that damage DNA. We also newly identified TOP2 as a factor involved in regulating GC genomic integrity and follicle atresia. This study has clinical implications for ovarian functional defects both for premenopausal cancer survivors and healthy women.
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