Fig. 9: A model illustrates how Top3β-TDRD3 complex and Top2β works together to promote NADT.

The model suggests that basal transcription produces low topological stress, so that the requirement for topoisomerases is low. Neuronal activity activates transcription of thousands of genes and enhancers, and thus induces a drastic increase of topological stress, including positive and negative supercoils, within a very short period. Top3β-TDRD3 complex is then recruited to these genes through Tudor domain-mediated interactions with arginine-methylated CTD of Pol II. Top3β can create transient SSBs to relax the negative supercoils generated during transcription and reduce R-loop formation (which inhibits transcription). Top1 can also generate transient SSBs to relax the positive supercoils. Transcription can then proceed normally. For some NER genes, there exist other topological barriers that prevent interactions between transcription machinery at enhancers and promoters. These genes require participation of Top2β to produce DSBs to overcome the topological barriers and enable assembly of activated transcription complex¹³. In the Top3β-mutant mice, global neuronal activity-activated transcription is impaired, due to failure to efficiently relieve topological stress. The affected genes include many that are important for neural development, mental health, and cognitive function. The defective transcription of these genes may contribute to the mental and cognitive disorders.