The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells

The ATM motif was previously shown to phosphorylate the BH3-only BID protein, a pro-apoptotic member of the BCL2 family. Using transgenic mice expressing a phosphodefective BID, Gross and colleagues find that the ATM effect on BID prevents its translocation to the mitochondria, where the effects of BID on ROS would trigger haematopoietic stem cells to exit quiescence. BID, a BH3-only BCL2 family member, functions in apoptosis as well as the DNA-damage response 1 . Our previous data demonstrated that BID is an ATM effector acting to induce cell-cycle arrest and inhibition of apoptosis following DNA damage 2 , 3 . Here we show that ATM-mediated BID phosphorylation plays an unexpected role in maintaining the quiescence of haematopoietic stem cells (HSCs). Loss of BID phosphorylation leads to escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo . We also demonstrate that BID phosphorylation plays a role in protecting HSCs from irradiation, and that regulating both quiescence and survival of HSCs depends on BID’s ability to regulate oxidative stress. Moreover, loss of BID phosphorylation, ATM knockout or exposing mice to irradiation leads to an increase in mitochondrial BID, which correlates with an increase in mitochondrial oxidative stress. These results show that the ATM–BID pathway serves as a critical checkpoint for coupling HSC homeostasis and the DNA-damage stress response to enable long-term regenerative capacity.