Distinctive Roles for FANCD2 and FANCJ in the Resection of Radiation-induced DNA Double-strand Breaks in Human Cells

Fanconi anemia (FA) patients are hypersensitive to ionizing radiation and other agents that generate DNA double-strand breaks (DSBs). The major error-free DSB repair pathway in human cells is homologous recombination (HR). In G2-phase cells, the decision to use HR to repair a DSB initiates DSB resection. Notably, siRNA-depletion of the FA protein FANCD2 reduces DSB end resection and RAD51-mediated recombination by 40%. In contrast, depletion of another FA protein FANCJ increases DSB resection and directs 77% more breaks into HR repair. However, FANCJ-depletion affects RAD51 protein production and/or stability, preventing the progression of recombination and HR repair. Taken together, data from this study and the literature suggest that FANCD2 is required in DSB resection where it localizes CtIP to the damaged chromatin and initiates HR. In contrast, FANCJ functions in regulating the proper processing and recombination of DSBs through its direct interaction with MRE11-nuclease and its intrinsic helicase activity.M.Sc