Genome-Wide Screens and Targeted Approaches

Abstract

The repair of mammalian DNA double-strand breaks (DSBs) by classi- cal non-homologous end joining (C-NHEJ) suppresses genomic instability and cancer and is required for development of the immune and nervous system. We hypothesize that proper repair of neural DSBs via C-NHEJ or other end-joining pathways is critical for neural functionality and homeostasis over time and that improper DSB repair could contribute to complex psychiatric and neurodegenera- tive diseases. Here, we summarize various findings made by our laboratory and others over the years that support this hypothesis. This evidence includes, most recently, our discovery of a set of genes, of which most serve neural functions, that can serve as targets of recurrent DSBs in primary neural stem and progenitor cells. We also present a speculative model, based on our findings, of mechanisms by which recurrent DSBs in neural genes can generate neuronal diversity and contrib- ute to neuropsychiatric disease.