Suppression of DSB Formation by Polβ in Active DNA Demethylation is Required for Postnatal Hippocampal Development

Abstract

AbstractGenome stability is essential for brain development and function. However, the contribution of DNA repair to genome stability in neurons remains elusive. Here, we demonstrate that the base excision repair protein Polβ is involved in hippocampal neuronal differentiation via a TET-mediated active DNA demethylation during early postnatal stages. Polβ deficiency induced extensive DNA double-strand breaks (DSBs) in hippocampal neurons, and a lesser extent in cortical neurons, during a period in which decreased levels of 5-methylcytosine were observed in genomic DNA. Inhibition of the hydroxylation of 5-methylcytosine by microRNAs miR29a/b-1 expression diminished DSB formation. Conversely, its induction by TET1 overexpression increased DSBs. The damaged hippocampal neurons exhibited aberrant neuronal gene expression profiles and dendrite formation. Behavioral analyses revealed impaired spatial learning and memory in adulthood. Thus, Polβ maintains genome stability in the active DNA demethylation that occurs during postnatal neuronal development, thereby contributing to differentiation and subsequent behavior.