Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6a, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA.
Mol Cancer Res. 2010 Jan;8(1):67-79. doi: 10.1158/1541-7786.MCR-09-0411. Epub 2010 Jan 12.
Base excision repair (BER) protein expression is important for resistance to DNA damage-induced cytotoxicity. Conversely, BER imbalance [DNA polymerase beta (Polbeta) 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 Polbeta 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 beta-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 Polbeta-deficient cells, suggesting a linkage between DNA repair, cell survival, and cellular bioenergetics.
碱基切除修复（BER）蛋白的表达对于抵抗 DNA 损伤诱导的细胞毒性很重要。相反，BER 失衡（DNA 聚合酶β（Polβ）缺乏或修复抑制）会增强辐射和化疗性 DNA 损伤药物的细胞毒性。尽管抑制 BER 途径的关键步骤会导致细胞毒性的 DNA 双链断裂积累，但我们报告称，由于 BER 蛋白 Polβ缺乏引起的 DNA 损伤诱导的细胞毒性会触发细胞死亡，这依赖于聚（ADP-核糖）（PAR）聚合酶的激活，但不依赖于 PAR 介导的凋亡诱导因子核易位或 PAR 糖基水解酶，表明细胞毒性不是来自 PAR 或 PAR 代谢物信号。细胞死亡可以通过 NAD（+）代谢物 β-烟酰胺单核苷酸挽救，并且与 NAD（+）生物合成的抑制协同作用，表明通过 BER 抑制介导的 DNA 损伤诱导的细胞毒性主要取决于细胞代谢物的生物利用度。我们为 Polβ 缺乏细胞中升高的烷化诱导细胞毒性提供了一种机制上的解释，表明 DNA 修复、细胞存活和细胞能量代谢之间存在联系。
