DNA damage response in neuronal homeostasis

Neurological deficits are found in many human genomic instability syndromes caused by a malfunction of the DNA damage response (DDR). MRE11, RAD50 and NBS1 form the MRN complex to activate ATM in response to DNA damages. Mutations of these molecules cause genomic instability syndromes, including A-TLD (MRE11 mutated), NBS (NBS1 mutated) and A-T (ATM mutated), among which neurological defects are common. It is well accepted that a dysfunction of a DDR pathway affects the proliferation and apoptosis of replicating neural cells. However, the diversity of neurological symptoms in these patients suggests an undiscovered function of these DDR molecules beyond their DDR roles in replicating cells.

In this project, we attempted to decipher the physiological function of these DDR molecules in postmitotic neurons using NBS1 knockout mouse models. Although NBS1 deletion is lethal to proliferating cells, it is dispensable for non-proliferating neurons. However, the ablation of NBS1 compromises neuron arborization and migration due to a dysregulated Notch1 signaling. We found that Nbs1 directly interacts with NICD1 and RBPJ and inhibits the Notch1 activity. This function of NBS1 is different from MRE11 and RAD50, differentiating it from the classical MRN-dependent DDR function. Nevertheless, DNA damage weakens the interaction of NBS1-NICD1 and thereby increases Notch1 activity. The genetic ablation or pharmaceutical inhibition of the Notch1 signaling can largely rescue the neuronal maturation and migration in vitro and in vivo. The functional interaction between Nbs1 and Notch1 defines a novel and physiological function of NBS1 in non-dividing cells and in neuropathological processes.