RAD51 Modulators Induce Mitotic Catastrophe in Aid Expressing Cells through Multiple Pathways

The B-cell specific DNA mutase/recombinase Activation Induced Cytidine Deaminase (AID) initiates DNA double strand breaks (DSB) necessary for immunoglobulin class switch recombination in activated B-cells. However, AID-induced DSBs are not restricted to immunoglobulin loci, and we previously demonstrated that the homologous recombination (HR) factor RAD51 is critical to repair widespread AID-initiated DSBs. While it is known that failure to properly repair AID-induced genomic DSBs is cytotoxic to B-cells, the pathways culminating in cell death were not fully known. Here, we demonstrate that AID-initiated DSBs can trigger mitotic catastrophe, a non-apoptotic cell death mechanism. Using genetic and chemical biology approaches we further show that AID-induced mitotic catastrophe involves multiple pathways, including mTOR. We also demonstrate that AID-induced cytotoxicity can be used to effectively and preferentially target AID-expressing lymphoid malignancies, in xenograft cancer model. This study reveals a cell death response to genomic damage by AID, providing new insight into the mechanisms that ensure cellular survival during B-cell maturation. Our findings support the idea that RAD51 modulation may be leveraged as a novel "synthetic lethal" therapeutic approach for treating AID-expressing malignancies, via the induction of mitotic catastrophe.