A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response

Abstract

SignificanceStress response pathways, such as the DNA damage response and the UPR, are critical in the etiology and treatment of cancer and other chronic diseases. Knowledge of an interplay between ER stress and genome damage repair is emerging, but evidence linking defective DNA repair and impaired ER stress response is lacking. Here, we show that AAG is necessary for UPR activation in response to alkylating agents. AAG-deficient mice and human cancer cells are impaired in alkylation-induced UPR. Strikingly, this defect can be complemented by an AAG variant defective in glycosylase activity. Our studies suggest that AAG has noncanonical functions and identify AAG as a point of convergence for stress response pathways. This knowledge could be explored to improve cancer treatment.