Author:
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.,Meira Lisiane B.
Abstract
AbstractDNA 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−/− cells treated with the alkylating agent methyl methanesulfonate (MMS). We show that, although Aag−/− cells display similar levels of alkylation-induced DNA breaks as wild type, PARP-1 activation is undetectable in AAG-deficient cells. Accordingly, Aag−/− 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−/− 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.
Funder
Qassim University
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Conselho Nacional de Desenvolvimento Científico e TecnolÓgico
Royal Society of Medicine
Publisher
Springer Science and Business Media LLC
Cited by
12 articles.
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