HR repair pathway plays a crucial role in maintaining neural stem cell fate under irradiation stress

Environmental stress can cause mutation or genomic instability in stem cells which, in some cases, leads to tumorigenesis. Mechanisms to monitor and eliminate these mutant stem cells remain elusive. Here, using the Drosophila larval brain as a model, we show that X-ray irradiation (IR) at the early larval stage leads to accumulation of nuclear Prospero (Pros), resulting in premature differentiation of neural stem cells (neuroblasts, NBs). Through NB-specific RNAi screenings, we determined that it is the Mre11-Rad50-Nbs1 complex and the homologous recombination (HR) repair pathway, rather than non-homologous endjoining pathway that plays, a dominant role in the maintenance of NBs under IR stress. The DNA damage sensor ATR/mei-41 is shown to act to prevent IR-induced nuclear Pros in a WRNexo-dependent manner. The accumulation of nuclear Pros in NBs under IR stress, leads to NB cell fate termination, rather than resulting in mutant cell proliferation. Our study reveals an emerging mechanism for the HR repair pathway in maintaining neural stem cell fate under irradiation stress.

Automated summary

Environmental stress can lead to mutation or genomic instability in stem cells, which can cause tumorigenesis. This study used the Drosophila larval brain as a model and found that X-ray irradiation leads to the accumulation of nuclear Prospero (Pros), resulting in premature differentiation of neural stem cells. Through RNAi screenings, it was determined that the Mre11-Rad50-Nbs1 complex and the homologous recombination repair pathway play a dominant role in maintaining neural stem cells under irradiation stress. The accumulation of nuclear Pros under irradiation stress leads to neural stem cell fate termination, rather than mutant cell proliferation. This study reveals a new mechanism for the homologous recombination repair pathway in maintaining neural stem cell fate under irradiation stress.