DNA repair in post-mitotic neurons: a gene-trapping strategy

DNA repair is essential for maintaining the integrity of the genome. Although mutation often occurs during meiosis and mitosis, the DNA of post-mitotic neurons is also under risk of damage, for example, from free radicals. For humans, given that the lifespan of post-mitotic neurons is many decades, competent DNA repair could be a critical factor in slowing ageing and the progression of some pathologies. Double-strand breaks (DSBs) are considered the most lethal form of DNA damage which, if left unrepaired, can cause cell death. Mammalian cells repair DSBs by two pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ). Although in vitro assays support the idea that the mature brain can repair DNA, repair of DSBs has not been directly demonstrated in living post-mitotic neurons. The aim of this study was to test directly the possibility of DSB repair in post-mitotic neurons by using a promoter-less gene-trapping (GT) vector. We found that granule cell primary cultures and cerebellar organotypic slices can integrate and express a promoter-less GT vector, thus revealing DNA repair activity in post-mitotic neurons. Furthermore, we showed that this activity increases after a mild apoptotic stimulus and correlates with an increased expression of both HR and NHEJ DNA repair factors.