Most adult stem cells, such as hematopoieticphase 3 stem cells (HSCs), are maintained within a quiescent or resting state in vivo. Quiescence is broadly thought of for being an important E3 Ligase protective mechanism for stem cells that minimizes endogenous tension induced by cellular respiration and DNA replication. We demonstrate that HSC quiescence may also have detrimental results. We observed that HSCs have unique cell-intrinsic mechanisms making certain their survival in response to ionizing irradiation (IR), which include enhanced prosurvival gene expression and solid activation of p53-mediated DNA harm response. We demonstrate that quiescent and proliferating HSCs are equally radioprotected but use various kinds of DNA restore mechanisms. We describe how nonhomologous finish joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities. Our benefits demonstrate that quiescence is actually a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.