Alkyladenine DNA glycosylase deficiency uncouples alkylation-induced strand break generation from PARP-1 activation and glycolysis inhibition

Alhumaydhi, Fahad A., de O. Lopes, Debora, Bordin, Diana L., Aljohani, Abdullah S. M., Lloyd, Cameron B., McNicholas, Michael D., Milano, Larissa, Charlier, Clara F., Villela, Izabel, Henriques, João Antonio P. et al, Plant, Kathryn E., Elliott, Ruan M. and Meira, Lisiane B. (2020) Alkyladenine DNA glycosylase deficiency uncouples alkylation-induced strand break generation from PARP-1 activation and glycolysis inhibition Scientific Reports, 10 (1).

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Abstract

DNA alkylation damage is repaired by base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG). Despite its role in DNA repair, AAG-initiated BER promotes cytotoxicity in a process dependent on poly (ADP-ribose) polymerase-1 (PARP-1); a NAD+-consuming enzyme activated by strand break intermediates of the AAG-initiated repair process. Importantly, PARP-1 activation has been previously linked to impaired glycolysis and mitochondrial dysfunction. However, whether alkylation affects cellular metabolism in the absence of AAG-mediated BER initiation is unclear. To address this question, we temporally profiled repair and metabolism in wild-type and Aag−^I− cells treated with the alkylating agent methyl methanesulfonate (MMS). We show that, although Aag−^I− cells display similar levels of alkylation-induced DNA breaks as wild type, PARP-1 activation is undetectable in AAG-deficient cells. Accordingly, Aag−^I− cells are protected from MMS-induced NAD+ depletion and glycolysis inhibition. MMS-induced mitochondrial dysfunction, however, is AAG-independent. Furthermore, treatment with FK866, a selective inhibitor of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT), synergizes with MMS to induce cytotoxicity and Aag−^I− cells are resistant to this combination FK866 and MMS treatment. Thus, AAG plays an important role in the metabolic response to alkylation that could be exploited in the treatment of conditions associated with NAD+ dysregulation.

Item Type:	Article
Divisions :	Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :	Name Email ORCID Alhumaydhi, Fahad A. de O. Lopes, Debora Bordin, Diana L. Aljohani, Abdullah S. M. Lloyd, Cameron B. McNicholas, Michael D. Milano, Larissa Charlier, Clara F. Villela, Izabel Henriques, João Antonio P. Plant, Kathryn E. Elliott, Ruan M. R.M.Elliott@surrey.ac.uk Meira, Lisiane B. L.Meira@surrey.ac.uk
Date :	10 February 2020
DOI :	10.1038/s41598-020-59072-6
Copyright Disclaimer :	Copyright 2020 The Authors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Depositing User :	Diane Maxfield
Date Deposited :	02 Oct 2020 12:42
Last Modified :	02 Oct 2020 12:42
URI:	http://epubs.surrey.ac.uk/id/eprint/858635

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