TOP2B

{{Short description|Protein-coding gene in the species Homo sapiens}}

DNA topoisomerase 2-beta is an enzyme that in humans is encoded by the TOP2B gene.{{cite journal | vauthors = Tan KB, Dorman TE, Falls KM, Chung TD, Mirabelli CK, Crooke ST, Mao J | title = Topoisomerase II alpha and topoisomerase II beta genes: characterization and mapping to human chromosomes 17 and 3, respectively | journal = Cancer Research | volume = 52 | issue = 1 | pages = 231–234 | date = January 1992 | pmid = 1309226 }}{{cite journal | vauthors = Jenkins JR, Ayton P, Jones T, Davies SL, Simmons DL, Harris AL, Sheer D, Hickson ID | display-authors = 6 | title = Isolation of cDNA clones encoding the beta isozyme of human DNA topoisomerase II and localisation of the gene to chromosome 3p24 | journal = Nucleic Acids Research | volume = 20 | issue = 21 | pages = 5587–5592 | date = November 1992 | pmid = 1333583 | pmc = 334390 | doi = 10.1093/nar/20.21.5587 }}

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.{{cite web | title = Entrez Gene: TOP2B topoisomerase (DNA) II beta 180kDa| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7155}}

=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.{{cite journal | vauthors = Li X, Marshall PR, Leighton LJ, Zajaczkowski EL, Wang Z, Madugalle SU, Yin J, Bredy TW, Wei W | display-authors = 6 | title = The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory | journal = The Journal of Neuroscience | volume = 39 | issue = 6 | pages = 970–983 | date = February 2019 | pmid = 30545945 | pmc = 6363930 | doi = 10.1523/JNEUROSCI.2024-18.2018 }} {{erratum|pmid=30545945|checked=yes}} 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.{{cite journal | vauthors = Dellino GI, Palluzzi F, Chiariello AM, Piccioni R, Bianco S, Furia L, De Conti G, Bouwman BA, Melloni G, Guido D, Giacò L, Luzi L, Cittaro D, Faretta M, Nicodemi M, Crosetto N, Pelicci PG | display-authors = 6 | title = Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations | journal = Nature Genetics | volume = 51 | issue = 6 | pages = 1011–1023 | date = June 2019 | pmid = 31110352 | doi = 10.1038/s41588-019-0421-z | s2cid = 159041612 | url = https://www.openaccessrepository.it/record/76042 | archive-url = https://web.archive.org/web/20220525082707/https://www.openaccessrepository.it/record/76042 | url-status = dead | archive-date = May 25, 2022 }}{{cite journal | vauthors = Singh S, Szlachta K, Manukyan A, Raimer HM, Dinda M, Bekiranov S, Wang YH | title = Pausing sites of RNA polymerase II on actively transcribed genes are enriched in DNA double-stranded breaks | journal = The Journal of Biological Chemistry | volume = 295 | issue = 12 | pages = 3990–4000 | date = March 2020 | pmid = 32029477 | pmc = 7086017 | doi = 10.1074/jbc.RA119.011665 | doi-access = free }} 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.{{cite journal | vauthors = Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH | display-authors = 6 | title = Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes | journal = Cell | volume = 161 | issue = 7 | pages = 1592–1605 | date = June 2015 | pmid = 26052046 | pmc = 4886855 | doi = 10.1016/j.cell.2015.05.032 }}

File:TOP2B NHEJ RNAP II double-strand break 2.jpg

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.{{cite journal | vauthors = Ju BG, Lunyak VV, Perissi V, Garcia-Bassets I, Rose DW, Glass CK, Rosenfeld MG | title = A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription | journal = Science | volume = 312 | issue = 5781 | pages = 1798–1802 | date = June 2006 | pmid = 16794079 | doi = 10.1126/science.1127196 | bibcode = 2006Sci...312.1798J | s2cid = 206508330 }} 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.{{cite journal | vauthors = Allen BL, Taatjes DJ | title = The Mediator complex: a central integrator of transcription | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 3 | pages = 155–166 | date = March 2015 | pmid = 25693131 | pmc = 4963239 | doi = 10.1038/nrm3951 }}

File:Brain regions in memory formation updated.jpg

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.{{cite journal | vauthors = Stott RT, Kritsky O, Tsai LH | title = Profiling DNA break sites and transcriptional changes in response to contextual fear learning | journal = PLOS ONE | volume = 16 | issue = 7 | pages = e0249691 | date = 2021 | pmid = 34197463 | pmc = 8248687 | doi = 10.1371/journal.pone.0249691 | bibcode = 2021PLoSO..1649691S | doi-access = free }}

=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.{{cite journal | vauthors = Nevin LM, Xiao T, Staub W, Baier H | title = Topoisomerase IIbeta is required for lamina-specific targeting of retinal ganglion cell axons and dendrites | journal = Development | volume = 138 | issue = 12 | pages = 2457–2465 | date = June 2011 | pmid = 21610027 | pmc = 3100707 | doi = 10.1242/dev.060335 }}

Interactions

TOP2B has been shown to interact with:

BAZ1B,{{cite journal | vauthors = Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S | display-authors = 6 | title = The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome | journal = Cell | volume = 113 | issue = 7 | pages = 905–917 | date = June 2003 | pmid = 12837248 | doi = 10.1016/s0092-8674(03)00436-7 | doi-access = free }}
HDAC1,{{cite journal | vauthors = Tsai SC, Valkov N, Yang WM, Gump J, Sullivan D, Seto E | title = Histone deacetylase interacts directly with DNA topoisomerase II | journal = Nature Genetics | volume = 26 | issue = 3 | pages = 349–353 | date = November 2000 | pmid = 11062478 | doi = 10.1038/81671 | s2cid = 19301396 }}{{cite journal | vauthors = Johnson CA, Padget K, Austin CA, Turner BM | title = Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis | journal = The Journal of Biological Chemistry | volume = 276 | issue = 7 | pages = 4539–4542 | date = February 2001 | pmid = 11136718 | doi = 10.1074/jbc.C000824200 | doi-access = free }}
Histone deacetylase 2,
P53,{{cite journal | vauthors = Cowell IG, Okorokov AL, Cutts SA, Padget K, Bell M, Milner J, Austin CA | title = Human topoisomerase IIalpha and IIbeta interact with the C-terminal region of p53 | journal = Experimental Cell Research | volume = 255 | issue = 1 | pages = 86–94 | date = February 2000 | pmid = 10666337 | doi = 10.1006/excr.1999.4772 }}
Small ubiquitin-related modifier 1{{cite journal | vauthors = Mao Y, Desai SD, Liu LF |author3-link=Leroy Liu | title = SUMO-1 conjugation to human DNA topoisomerase II isozymes | journal = The Journal of Biological Chemistry | volume = 275 | issue = 34 | pages = 26066–26073 | date = August 2000 | pmid = 10862613 | doi = 10.1074/jbc.M001831200 | doi-access = free }} and
T-cell surface glycoprotein CD3 epsilon chain.{{cite journal | vauthors = Nakano H, Yamazaki T, Miyatake S, Nozaki N, Kikuchi A, Saito T | title = Specific interaction of topoisomerase II beta and the CD3 epsilon chain of the T cell receptor complex | journal = The Journal of Biological Chemistry | volume = 271 | issue = 11 | pages = 6483–6489 | date = March 1996 | pmid = 8626450 | doi = 10.1074/jbc.271.11.6483 | doi-access = free }}

In other species

In Drosophila Hadlaczky et al. 1988 found DNA topoisomerase II β did not correlate with cell proliferation - while α did.{{cite journal | vauthors = Wang JC | title = DNA topoisomerases | journal = Annual Review of Biochemistry | volume = 65 | issue = 1 | pages = 635–692 | year = 1996 | pmid = 8811192 | doi = 10.1146/annurev.bi.65.070196.003223 | publisher = Annual Reviews }}