TOP2B

DNA topoisomerase 2-beta is an enzyme that in humans is encoded by the TOP2B gene.

TOP2B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3QX3, 4G0U, 4G0V, 4G0W, 4J3N
Identifiers
Aliases	TOP2B, TOPIIB, top2beta, topoisomerase (DNA) II beta, DNA topoisomerase II beta, BILU
External IDs	OMIM: 126431; MGI: 98791; HomoloGene: 134711; GeneCards: TOP2B; OMA:TOP2B - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3p24.2 Start 25,597,984 bp End 25,664,907 bp
Gene location (Mouse) Chr. Chromosome 14 (mouse) Band 14|14 A1 Start 6,034,301 bp End 6,104,584 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence ventricular zone endothelial cell Achilles tendon cerebellar cortex cerebellar hemisphere right hemisphere of cerebellum retinal pigment epithelium epithelium of colon rectum Top expressed in ventricular zone ganglionic eminence tail of embryo medial ganglionic eminence genital tubercle thymus abdominal wall dermis condyle lobe of cerebellum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity nucleotide binding DNA binding histone deacetylase binding chromatin binding isomerase activity metal ion binding DNA topoisomerase activity protein C-terminus binding protein heterodimerization activity enzyme binding ATP binding protein kinase C binding ribonucleoprotein complex binding Cellular component cytosol nucleoplasm heterochromatin nucleolus nucleus cytoplasm ribonucleoprotein complex viral integration complex Biological process resolution of meiotic recombination intermediates axonogenesis DNA metabolic process neuron migration forebrain development mitotic DNA integrity checkpoint signaling sister chromatid segregation DNA topological change positive regulation of single stranded viral RNA replication via double stranded DNA intermediate Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7155 21974 Ensembl ENSG00000077097 ENSMUSG00000017485 UniProt Q02880 Q64511 RefSeq (mRNA) NM_001068 NM_001330700 NM_009409 RefSeq (protein) NP_001059 NP_001317629 NP_033435 Location (UCSC) Chr 3: 25.6 – 25.66 Mb Chr 14: 6.03 – 6.1 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Function

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, for example mitoxantrone, 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 of this gene results in two transcript variants; however, the second variant has not yet been fully described.

Neuronal activity

During a new learning experience, a set of genes is rapidly expressed in the brain. This induced gene expression is considered to be essential for processing the information being learned. Such genes are referred to as immediate early genes (IEGs). TOP2B activity is essential for the expression of IEGs in a type of learning experience in mice termed associative fear memory. Such a learning experience appears to rapidly trigger TOP2B to induce double-strand breaks in the promoter DNA of IEG genes that function in neuroplasticity. Repair of these induced breaks is associated with DNA demethylation of IEG gene promoters allowing immediate expression of these IEG genes.

Activation of more than 600 regulatory sequences in promoters and 800 regulatory sequences in enhancers, in many cell types, appears to depend on short-term double-strand breaks initiated by TOP2B. The induction of particular double-strand breaks are specific with respect to their inducing signal. When neurons are activated in vitro, just 22 of TOP2B-induced double-strand breaks occur in their genomes, largely at immediate early genes.

The induction of short-term double-strand breaks by TOP2B occurs in association with at least four enzymes of the non-homologous end joining (NHEJ) DNA repair pathway (DNA-PKcs, KU70, KU80 and DNA LIGASE IV) (see Figure). These enzymes repair the double-strand breaks within about 15 minutes to two hours. The double-strand breaks in the promoter are thus associated with TOP2B and at least these four repair enzymes. These proteins are present simultaneously on a single promoter nucleosome (there are about 147 nucleotides in the DNA sequence wrapped around a single nucleosome) located near the transcription start site of their target gene.

The double-strand break introduced by TOP2B apparently frees a part of the promoter at an RNA polymerase-bound transcription start site to physically move to its associated enhancer (see regulatory sequence). This allows the enhancer, with its bound transcription factors and mediator proteins, to directly interact with the RNA polymerase paused at the transcription start site to start transcription.

Brain regions involved in memory formation including medial prefrontal cortex (mPFC)

Contextual fear conditioning in the mouse causes the mouse to have a long-term memory and fear of the location in which it occurred. This conditioning causes hundreds of gene-associated DSBs in the medial prefrontal cortex (mPFC) and hippocampus that are important for learning and memory.

Other TOP2B and DNA interactions

Interactions of TOP2B and DNA also regulate transcription of genes that are important for development. These include genes encoding axon guidance factors and cell adhesion molecules. Specifically, TOP2B is required for lamina-specific targeting of retinal ganglion cell axons and dendrites in the zebrafish.

Interactions

TOP2B has been shown to interact with:

• BAZ1B,
• HDAC1,
• Histone deacetylase 2,
• P53,
• Small ubiquitin-related modifier 1 and
• T-cell surface glycoprotein CD3 epsilon chain.

In other species

In Drosophila Hadlaczky et al. 1988 found DNA topoisomerase II β did not correlate with cell proliferation - while α did.

Further reading

• Champoux JJ (2002). "DNA topoisomerases: structure, function, and mechanism". Annual Review of Biochemistry. 70: 369–413. doi:10.1146/annurev.biochem.70.1.369. PMID 11395412.
• Austin CA, Fisher LM (June 1990). "Isolation and characterization of a human cDNA clone encoding a novel DNA topoisomerase II homologue from HeLa cells". FEBS Letters. 266 (1–2): 115–117. doi:10.1016/0014-5793(90)81520-X. PMID 2163884. S2CID 46581515.
• Chung TD, Drake FH, Tan KB, Per SR, Crooke ST, Mirabelli CK (December 1989). "Characterization and immunological identification of cDNA clones encoding two human DNA topoisomerase II isozymes". Proceedings of the National Academy of Sciences of the United States of America. 86 (23): 9431–9435. Bibcode:1989PNAS...86.9431C. doi:10.1073/pnas.86.23.9431. PMC 298510. PMID 2556712.
• Austin CA, Sng JH, Patel S, Fisher LM (March 1993). "Novel HeLa topoisomerase II is the II beta isoform: complete coding sequence and homology with other type II topoisomerases". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1172 (3): 283–291. doi:10.1016/0167-4781(93)90215-Y. PMID 8383537.
• Davies SL, Jenkins JR, Hickson ID (August 1993). "Human cells express two differentially spliced forms of topoisomerase II beta mRNA". Nucleic Acids Research. 21 (16): 3719–3723. doi:10.1093/nar/21.16.3719. PMC 309874. PMID 8396237.
• Nakano H, Yamazaki T, Miyatake S, Nozaki N, Kikuchi A, Saito T (March 1996). "Specific interaction of topoisomerase II beta and the CD3 epsilon chain of the T cell receptor complex". The Journal of Biological Chemistry. 271 (11): 6483–6489. doi:10.1074/jbc.271.11.6483. PMID 8626450.
• Biersack H, Jensen S, Gromova I, Nielsen IS, Westergaard O, Andersen AH (August 1996). "Active heterodimers are formed from human DNA topoisomerase II alpha and II beta isoforms". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8288–8293. Bibcode:1996PNAS...93.8288B. doi:10.1073/pnas.93.16.8288. PMC 38663. PMID 8710863.
• Meyer KN, Kjeldsen E, Straub T, Knudsen BR, Hickson ID, Kikuchi A, et al. (February 1997). "Cell cycle-coupled relocation of types I and II topoisomerases and modulation of catalytic enzyme activities". The Journal of Cell Biology. 136 (4): 775–788. doi:10.1083/jcb.136.4.775. PMC 2132491. PMID 9049244.
• Fukunaga R, Hunter T (April 1997). "MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates". The EMBO Journal. 16 (8): 1921–1933. doi:10.1093/emboj/16.8.1921. PMC 1169795. PMID 9155018.
• Ng SW, Liu Y, Schnipper LE (December 1997). "Cloning and characterization of the 5'-flanking sequence for the human DNA topoisomerase II beta gene". Gene. 203 (2): 113–119. doi:10.1016/S0378-1119(97)00500-3. PMID 9426241.
• Yamane K, Kawabata M, Tsuruo T (December 1997). "A DNA-topoisomerase-II-binding protein with eight repeating regions similar to DNA-repair enzymes and to a cell-cycle regulator". European Journal of Biochemistry. 250 (3): 794–799. doi:10.1111/j.1432-1033.1997.00794.x. PMID 9461304.
• Cowell IG, Willmore E, Chalton D, Marsh KL, Jazrawi E, Fisher LM, Austin CA (September 1998). "Nuclear distribution of human DNA topoisomerase IIbeta: a nuclear targeting signal resides in the 116-residue C-terminal tail". Experimental Cell Research. 243 (2): 232–240. doi:10.1006/excr.1998.4150. PMID 9743583.
• Lang AJ, Mirski SE, Cummings HJ, Yu Q, Gerlach JH, Cole SP (October 1998). "Structural organization of the human TOP2A and TOP2B genes". Gene. 221 (2): 255–266. doi:10.1016/S0378-1119(98)00468-5. PMID 9795238.
• Sng JH, Heaton VJ, Bell M, Maini P, Austin CA, Fisher LM (March 1999). "Molecular cloning and characterization of the human topoisomerase IIalpha and IIbeta genes: evidence for isoform evolution through gene duplication". Biochimica et Biophysica Acta. 1444 (3): 395–406. doi:10.1016/S0167-4781(99)00020-2. PMID 10095062.
• Bjergbaek L, Jensen S, Westergaard O, Andersen AH (September 1999). "Using a biochemical approach to identify the primary dimerization regions in human DNA topoisomerase IIalpha". The Journal of Biological Chemistry. 274 (37): 26529–26536. doi:10.1074/jbc.274.37.26529. PMID 10473615.
• Cowell IG, Okorokov AL, Cutts SA, Padget K, Bell M, Milner J, Austin CA (February 2000). "Human topoisomerase IIalpha and IIbeta interact with the C-terminal region of p53". Experimental Cell Research. 255 (1): 86–94. doi:10.1006/excr.1999.4772. PMID 10666337.
• Mao Y, Desai SD, Liu LF (August 2000). "SUMO-1 conjugation to human DNA topoisomerase II isozymes". The Journal of Biological Chemistry. 275 (34): 26066–26073. doi:10.1074/jbc.M001831200. PMID 10862613.
• Mirski SE, Voskoglou-Nomikos T, Young LC, Deeley RG, Campling BG, Gerlach JH, Cole SP (June 2000). "Simultaneous quantitation of topoisomerase II alpha and beta isoform mRNAs in lung tumor cells and normal and malignant lung tissue". Laboratory Investigation; A Journal of Technical Methods and Pathology. 80 (6): 787–795. doi:10.1038/labinvest.3780083. PMID 10879730.