Differential function of NBS1 and ATR in neurogenesis

MRN (MRE11/RAD50/NBS) helps to activate ATM in response to DNA double strand breaks (DSBs) and also facilitates ATR activation by catalyzing the formation and extension of DNA single strand breaks (SSBs). Mutations of NBS1 and ATR cause human genomic instability syndrome NBS and ATR-Seckel, respectively, both of which feature neurodevelopmental defects. Whether these two DNA damage response components interact to prevent neuropathology is largely unknown. Here we show that a deletion of Nbs1 or Atr in the mouse central nervous system (CNS) results in neurodevelopmental defects characterized by reduced proliferation and increased apoptosis in embryonic brains. In contrast to Nbs1, deletion of Atr alone and both Nbs1 and Atr in the CNS causes early postnatal lethality, indicating a wider function of Atr. Importantly, deletion of Nbs1 and Atr together results in dramatic proliferation defects in neuroprogenitors. Whereas most apoptosis in the Nbs1-deleted cortex is restricted to the highly proliferating progenitors, Atr knockout induces apoptosis in both proliferating and non-proliferating neural cells. Consistently, an inducible deletion of Atr or Nbs1–Atr, but not of Nbs1, triggers a p53-independent cell death pathway in differentiated neurons, albeit elevated DNA damage in Nbs1 null neurons. Altogether, we identify a distinct function of Nbs1 and Atr in neurogenesis, namely a specific function of Nbs1 in proliferating neuroprogenitors and of Atr in both proliferating and non-dividing cells.

► Deletion of Atr or both Atr and Nbs1 in mouse central nervous system causes brain atrophy and early postnatal lethality.
► Deletion of Atr and Nbs1 reduces neuroprogenitor proliferation.
► Nbs1 knockout triggers apoptosis only in proliferating neuroprogenitors.
► Atr null mutation induces apoptosis in both proliferating neuroprogenitors and also in postmitotic neurons.