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

Abstract

Early work from about two decades ago implicated DNA double-strand break (DSB) formation and repair in neuronal development. Findings emerging from recent studies of DSBs in proliferating neural progenitors and in mature, non-dividing neurons suggest important roles of DSBs in brain physiology, aging, cancer, psychiatric and neurodegenerative disorders. We provide an overview of some findings and speculate on what may lie ahead.

Keywords: Copy number variations; DNA double-strand breaks; DNA repair; DNA replication; Exon shuffling; Genomic instability; Neural stem and progenitor cells; Neurodevelopment; Neurons; Non-homologous end joining; Somatic mosaicism; Transcription.

Figure 1.. Hypothetical model of replication stress-induced, DSB-mediated RDCgene rearrangements in neural stem/progenitor cells.

(A) RDC-genes often contain very large introns and small exons (not drawn to scale). Joining of separate, intronic DSBs (indicated by black arrowheads, top) would result in exon deletions and RDC-gene diversification (bottom). In the model shown, exons 3 and 4 are deleted via end-joining of two intronic DSBs (dotted lines), with the resulting breakpoint junction indicated by a dashed box. 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. Adapted from [55]. The three intron phases (1,2,0) are shown. Exons flanked by introns of the same phase (0–0, 1–1, 2–2) can be joined without shifting the reading frame. (C) Annotation of intron phases in RDC-genes Ctnna2 and Cadm2. Black rectangles indicate exons. First coding exon is shown in orange.