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

Abstract

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 theDrosophilalarval 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 end-joining pathway that plays, a dominant role in the maintenance of NBs under IR stress. The DNA damage sensor ATR/mei-41is 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.

ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

“…Interestingly, earlier work has shown that deletion of Atr in adult mice leads to depletion of stem and progenitor cells ( 63 ), that has been suggested to arise due to aberrant, ectopic differentiation. This hypothesis is supported by a recent report in the fruitfly, which identified a critical role for Drosophila ATR ( mei-41 ) in preventing neuroblast differentiation in response to irradiation stress ( 64 ). Interestingly, inhibition of the ATR and ATM DDR kinases has been linked with differentiation in acute myeloid leukemia cells carrying MLL fusion proteins, where treatment with ATR inhibitors led to terminal differentiation and loss of leukemic blasts ( 65 , 66 ).…”

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

“…This loss of stem and progenitor cells has been suggested to arise due to elevated apoptosis or senescence, however, no differences could be observed between Atr -deficient and control tissues, raising the possibility that deletion of Atr triggered aberrant, ectopic differentiation, leading to the loss of proliferating stem and progenitor cells. This hypothesis is supported by a recent report in the fruit fly, Drosophila melanogaster , that identified a critical role for Drosophila ATR ( mei-41 ) in preventing neuroblast differentiation in response to irradiation stress 64 .…”

The role of DNA damage in neural stem cells ageing

“…Conversely, knocking down all HR repair pathway genes (such as RAD50, Nbs) leads to significantly enhanced premature differentiation of NSCs, which is indicative of premature ageing. These findings suggest that HR plays an important role in NSCs DDR when NHEJ is nonfunctional (Xu et al, 2023). It is also demonstrated that NSCs, when subjected to destruction of Rad54 (homologous recombination factor), led to a stagnant phase in the G2/S and extended S phase.…”

“…When exposed to low levels of radiation, NSCs tend to differentiate prematurely rather than undergo apoptosis like most differentiated cells, indicating their tolerance to DNA damage. NSCs exhibit higher DNA damage tolerance compared to differentiated cells (Xu et al, 2023). Liu Z et al found that Dgcr8 −/− NSCs did not show increased apoptosis, but they did after differentiation into neurons or oligodendrocytes.…”