DNA damage-mediated genome instability is a contributing factor in the causation of human diseases, including neurodegeneration, immunological disorders, and cancer. Understanding how cells prevent and manage DNA damage is highly significant. Pathological accumulation of R loops, transcription-linked 3 nucleic-acid structure consisting of a RNA:DNA hybrid and a displaced single-strand DNA (ssDNA), causes genomic instability upon its cleavage into DNA double strand breaks (DSBs). Using a PID disease model of human Wiskott-Aldrich syndrome (WAS), we recently discovered an essential nuclear role of WASp, the protein deficient in WAS, in preventing R loop-mediated DNA DSBs in T lymphocytes. Others discovered impaired repair of DSBs from deficient homology-directed repair (HDR) in WAS B cells. Together, the evidence suggest that WAS T and B lymphocytes are poorly-equipped to both prevent and resolve DSBs sustained from the genomic stress of transcription, ionizing-radiation, and chemotherapy. We recently uncovered an additional, essential function of WASp in coordinating the cell-protective Golgi dispersal response (GDR) induced by DNA DSBs in human T and B cells. These studies have dramatically expanded the field of play for WASp, from historically an Arp2/3-mediated modifier of actin in the cytoplasm to now supporting a novel, essential function(s) of stabilizing the genome in the nucleus.