This review discusses the dual role of DNA double-strand breaks (DSBs) in the brain, where they can act as both physiological regulators of gene expression and contributors to neuronal dysfunction under pathological conditions. In post-mitotic neurons, which rely mainly on non-homologous end joining, the balance between DSB formation and repair appears to be especially important. Recent studies show that transient activity-induced DSBs, particularly at regulatory regions of immediate early genes (IEGs), support chromatin remodeling and transcriptional activation. In contrast, persistent DSBs associated with chronic stress, hyperexcitability, ageing, or neurodegenerative disorders are linked to impaired repair, prolonged DNA damage response signaling, neuroinflammation, and stable transcriptional alterations. Available findings also suggest that glial cells participate in DSB-related responses to stress, although these mechanisms remain less clearly understood than those in neurons. Overall, current evidence supports the view that the functional outcome of DSBs in the brain depends on their genomic context, duration, and efficiency of repair. The integration of DSB mapping with transcriptomic and epigenomic profiling may help to identify early transitions from adaptive to maladaptive DNA damage responses (DDR) in neurons and glia.
Shalaginova et al. (Thu,) studied this question.