Data from Bioenergetic Metabolites Regulate Base Excision Repair–Dependent Cell Death in Response to DNA Damage
Year: 2023
Type: other
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
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4362491838