The nonhomologous end-joining (NHEJ) pathway of DNA repair is required for neurodevelopment. Mice deficient in NHEJ proteins exhibit extensive NPC apoptosis and often die prenatally (27). Intriguingly, the embryonic lethality and NPC apoptosis phenotypes are rescued in a p53-null mouse background, suggesting that genotoxic stress contributes to lethality (28). Consistent with these data, compound heterozygous mutations in DNA damage response genes [e.g., ataxia telangiectasia mutated (ATM), ataxia telangiectasia-related (ATR), and ATR-interacting protein (ATRIP)] can lead to increased mutational loads, neurodevelopmental brain defects, and neuronal degeneration (29–31). More broadly, deficits in other DNA repair pathways, such as transcription-coupled repair, homologous recombination, and nucleotide excision repair, also can lead to human neurodevelopmental phenotypes (32, 33).
