Recurrently Breaking Genes in Neural Progenitors: Potential Roles of DNA Breaks in Neuronal Function, Degeneration and Cancer

Abstract

The repair of mammalian DNA double-strand breaks (DSBs) by classical 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 neurodegenerative 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 contribute to neuropsychiatric disease.Early studies revealed that the lymphocyte-specific V(D)J recombination reaction involves the introduction of DNA double-stranded breaks (DSBs) at the ends of antigen receptor V, D, and J gene segments, followed by the processing of the

Three classes of recurrent DNA break clusters in brain progenitors identified by 3D proximity-based break joining assay

“…For RDC genes lying within a specific topologic domain, two RDC gene DSBs would mostly be either rejoined or joined to other DSBs within different introns of the same RDC gene-the latter of which could functionally alter encoded proteins (28). In this regard, while many RDC genes are thought to produce numerous protein isoforms via differential RNA processing (29,30), such plasticity conceivably could be augmented or "hardwired" by intragenic rearrangements (28). In this context, 30 RDCs, including the previously described nine RDCs (16), locate in CNV regions found in single human neurons (10) (SI Appendix, Fig.…”

Protective Mechanisms Against DNA Replication Stress in the Nervous System

“…Replication stress may generate genomic instability in the developing nervous system, and the importance of the replication stress response (RSR) pathways for the CNS formation has been demonstrated by many studies [13][14][15][16][17][18]. In addition, evidence that the RSR alters the cellular microenvironment and regulates immune responses has also accumulated rapidly [19,20].…”

DNA double-strand breaks as drivers of neural genomic change, function, and disease

“…As indicated above, preferential DSB joining promoted by topological domains drives IgH CSR [37, 38], which involves joining of two DSBs over genomic distances of 100 kb or more, and deletion of the intervening DNA sequence [4]. Based on the estimated high frequency of DSBs in RDC-genes upon replication stress [14], we propose that separate, intronic DSBs within long RDC-genes are frequently joined to each other, thus potentially leading to gene diversification in NSPCs [51] (Figure 1A).…”

“…Intragenic joining of DSBs is expected to be promoted by location of RDC-genes within topologically associated domains. Adapted from [51]. (B) Illustration of intron phases.…”