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

Autor:	Milano L; Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7WG Guildford, United Kingdom.; Center of Biotechnology, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Brazil.; Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Center, Quebec City, QC G1V 0A6, Canada., Charlier CF; Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7WG Guildford, United Kingdom., Andreguetti R; Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7WG Guildford, United Kingdom., Cox T; Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7WG Guildford, United Kingdom., Healing E; Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom., Thomé MP; Department of Biophysics, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Brazil., Elliott RM; Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom., Samson LD; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Masson JY; Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Center, Quebec City, QC G1V 0A6, Canada., Lenz G; Center of Biotechnology, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Brazil.; Department of Biophysics, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Brazil., Henriques JAP; Center of Biotechnology, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Brazil.; Department of Biophysics, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Brazil., Nohturfft A; Molecular and Clinical Sciences Research Institute, St. George's University of London, SW17 0RE London, United Kingdom., Meira LB; Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7WG Guildford, United Kingdom; l.meira@surrey.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Mar 01; Vol. 119 (9).
DOI:	10.1073/pnas.2111404119
Abstrakt:	Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation affects global cellular stress responses is sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver, using mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by XBP1, a key UPR effector. Importantly, this response is significantly reduced in the Aag knockout. To investigate how AAG affects alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cells expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, AAG knockdown compromised UPR induction and led to a defect in XBP1 activation. To verify the requirements for the DNA repair activity of AAG in this response, AAG knockdown cells were complemented with wild-type Aag or with an Aag variant producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective Aag does not fully protect AAG knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, besides its enzymatic activity, AAG has noncanonical functions in alkylation-induced UPR that contribute to cellular responses to alkylation. Competing Interests: The authors declare no competing interest. (Copyright © 2022 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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