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DNA topoisomerase 2-beta is an enzyme that in humans is encoded by the TOP2Bgene.[5][6]
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.[7]
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.[8] 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.[8]
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.[9][10] 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.[11]
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.[11][12] 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.[12]
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.[14]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Tan KB, Dorman TE, Falls KM, Chung TD, Mirabelli CK, Crooke ST, Mao J (January 1992). "Topoisomerase II alpha and topoisomerase II beta genes: characterization and mapping to human chromosomes 17 and 3, respectively". Cancer Research. 52 (1): 231–234. PMID1309226.
^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. PMID10666337.
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. PMID8383537.
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. PMID9426241.
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. PMID9743583.
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. PMID9795238.
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. PMID10095062.
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. PMID10666337.
