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Supplementary Data from Bioenergetic Metabolites Regulate Base Excision Repair–Dependent Cell Death in Response to DNA Damage

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posted on 2023-04-03, 18:00 authored by Jiang-bo Tang, Eva M. Goellner, Xiao-hong Wang, Ram N. Trivedi, Claudette M. St Croix, Elena Jelezcova, David Svilar, Ashley R. Brown, Robert W. Sobol
Supplementary Data from Bioenergetic Metabolites Regulate Base Excision Repair–Dependent Cell Death in Response to DNA Damage

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ARTICLE ABSTRACT

Base excision repair (BER) protein expression is important for resistance to DNA damage–induced cytotoxicity. Conversely, BER imbalance [DNA polymerase β (Polβ) deficiency or repair inhibition] enhances cytotoxicity of radiation and chemotherapeutic DNA-damaging agents. Whereas inhibition of critical steps in the BER pathway result in the accumulation of cytotoxic DNA double-strand breaks, we report that DNA damage–induced cytotoxicity due to deficiency in the BER protein Polβ triggers cell death dependent on poly(ADP-ribose) (PAR) polymerase activation yet independent of PAR-mediated apoptosis-inducing factor nuclear translocation or PAR glycohydrolase, suggesting that cytotoxicity is not from PAR or PAR catabolite signaling. Cell death is rescued by the NAD+ metabolite β-nicotinamide mononucleotide and is synergistic with inhibition of NAD+ biosynthesis, showing that DNA damage–induced cytotoxicity mediated via BER inhibition is primarily dependent on cellular metabolite bioavailability. We offer a mechanistic justification for the elevated alkylation-induced cytotoxicity of Polβ-deficient cells, suggesting a linkage between DNA repair, cell survival, and cellular bioenergetics. Mol Cancer Res; 8(1); 67–79