section_path: Genetics/DNA topoisomerase 2-beta in learning and memory
section_name: DNA topoisomerase 2-beta in learning and memory
paragraph_text: DNA topoisomerase 2-beta in learning and memory
  
  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). DNA topoisomerase 2-beta (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.
  
  The double-strand breaks that are induced during a learning experience are not immediately repaired. About 600 regulatory sequences in promoters and about 800 regulatory sequences in enhancers appear to depend on double strand breaks initiated by topoisomerase 2-beta (TOP2B) for activation. 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.
  
  Such TOP2B-induced double-strand breaks are accompanied by 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 the 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.
  
  Contextual fear conditioning in the mouse causes the mouse to have a long-term memory and fear of the location in which it occurred. Contextual fear conditioning causes hundreds of DSBs in mouse brain medial prefrontal cortex (mPFC) and hippocampus neurons (see Figure: Brain regions involved in memory formation). These DSBs predominately activate genes involved in synaptic processes, that are important for learning and memory.