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

• DOI: 10.1073/pnas.2111404119
• Publication Date: 2022-02-23T22:45:41Z
• Authors: Larissa Milano; Clara F. Charlier; Rafaela Andreguetti; Thomas Cox; Eleanor Healing; Marcos P. Thomé; Ruan M. Elliott; Leona D. Samson; Jean-Yves Masson; Guido Lenz; João Antonio P. H...; Axel Nohturfft; Lisiane B. Meira
• Keywords: XBP1; Methyl methanesulfonate; Cellular stress response

Alkylating agents damage DNA and proteins are widely used in cancer chemotherapy. While cellular responses to alkylation-induced have been explored, knowledge of how alkylation affects global stress is sparse. Here, we examined the effects alkylating agent methylmethane sulfonate (MMS) on gene expression mouse liver, using mice deficient alkyladenine glycosylase (Aag), enzyme that initiates repair alkylated bases. MMS induced a robust transcriptional response wild-type liver included markers endoplasmic reticulum (ER) stress/unfolded protein (UPR) known be controlled by XBP1, key UPR effector. Importantly, this significantly reduced