Figure 1. Sources of DNA damage in the brain.

Transcriptional activities can result in topoisomerase cleavage complexes, which lead to the induction of SSBs or DSBs depending upon the topoisomerase in question. Additionally, metabolic activity by mitochondria generate ROS, which can scar DNA bases with oxidative modifications. Although less common in the adult brain, cell division is also a source of DNA damage. Proliferation increases the chance of replication fork and transcription complex collision, thereby inducing DSBs. In the developing brain, this is a particular risk for NPCs, which harbor increased translocations in long genes (where these collisions are most likely to occur) important for neuronal function. Cognitively demanding tasks recruit specific neuronal ensembles whose plasticity is highly dependent upon immediate early gene transcription. Therefore, neurons generate topoisomerase II‐mediated DSBs in response to learning and memory. Finally, the proteins responsible for various neurodegenerative diseases have also been found to play roles in DNA damage detection and repair. (Created with BioRender.com).