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Department of Biological SciencesRAD51 is one of the major players in homologous recombination (HR) for repairing double-strand breaks (DSBs) and also protects replication forks (RFs) for genome maintenance to suppress tumors. RAD51 should be tightly regulated by post-translational modifications (PTMs) or protein-protein interactions to prevent unscheduled HR. c-Abl tyrosine kinase sequentially phosphorylates RAD51 at Y315 and Y54 in response to ionizing radiation (IR). However, the functional significance of these phosphorylations remained elusive. In leukemia cells, BCR-ABL, oncogenic tyrosine kinase constitutively phosphorylates RAD51, but it is unclear what the consequence of such constitutive phosphorylation is in leukemic cells and its impact on genome maintenance or potentially in tumor progression and drug resistance. In this study, Rad51 knock-in (KI) mouse embryonic stem (ES) cell lines and Rad51 Y315F genetically-modified mouse were analyzed to define the roles of Rad51 tyrosine phosphorylation in vivo. I found the followings: 1) RAD51 Y315 residue is phosphorylated by BCRABL in cells 2) the Y54 phosphorylation of RAD51 significantly reduced the formation of IR-induced eGFP-hRAD51 foci (HR defect) 3) Phosphorylation of RAD51 impaired RAD51 self-interaction 4) Overexpression of either RAD51 Y54E or Y315E decreased I-SceI induced DSB repair 5) Rad51 Y315F knock-in mouse increased genomic instability in response to low-dose IR. Taken together, RAD51 tyrosine phosphorylations play roles in DSB repair to maintain genomic integrity.clos