Fe65 in the response to DNA damage

The function of the b-amyloid precursor protein APP is still not completely understood. A possible starting point to address the question of the function of APP is the well demonstrated interaction of its cytodomain with the adaptor protein Fe65. The phenotype of Fe65 KO mice suggested that this protein could play some role in DNA damage response (DDR). In fact, Fe65 null mice show high sensitivity to DNA damaging agents. Furthermore suppression of Fe65 in cultured cells hampers DNA repair. Strong evidence indicates that DDR could be a crucial barrier against cell transformation. To address the possibility that Fe65 could be involved in tumorigenesis, we examined the effect of Fe65 suppression in cell transformation. We observed that Fe65 knockdown resulted in a significant increase in the number of colonies of NIH3T3 cells transformed by oncogenic Ras. This phenotype was rescued by wild type Fe65 but not by Fe65 mutant unable to interact with Tip60 histone acetyl-transferase. Experiments in mouse models of tumorigenesis confirmed the apparent role of Fe65 as a tumor suppressor. Indeed, haploinsufficiency of Fe65 greatly accelerated the appearance of the lymphomas in tEl-myc mice. The weakening of DDR provoked by Fe65 haploinsufficiency was confirmed in cells treated with IR or DNA damaging agents or transiently transfected with Myc, thus suggesting that Fe65 suppression affects tumorigenesis by hampering DDR. Further experiments in vitro and in vivo suggest that ligands of the central PTB of Fe65, like Tip60, play a crucial role in the function of chromatin-associated Fe65.