We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N ² -(1-carboxyethyl)-2'-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α-mediated transcription of NER genes via enhanced 2-ketoglutarate-dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.

中文翻译：

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升高的葡萄糖通过抑制核苷酸切除修复来增加基因组的不稳定性。

我们研究了升高的葡萄糖可能促进基因组不稳定性的潜在机制。基因表达研究、蛋白质测量、质谱分析和功能分析表明，升高的葡萄糖会抑制核苷酸切除修复 (NER) 途径，促进 DNA 链断裂，并增加 DNA 糖化加合物N ^{2 的水平}-(1-羧乙基)-2'-脱氧鸟苷(CEdG)。NER 感受态细胞中的糖化应激产生单链断裂，伴随着 ATR 激活、γH2AX 诱导和增强的非同源末端连接和同源定向修复。在 NER 缺陷细胞中，糖化应激激活 ATM/ATR/H2AX，与双链断裂形成一致。升高的葡萄糖通过增强 2-酮戊二酸依赖性脯氨酰羟化酶 (PHD) 活性减弱缺氧诱导因子 1α 介导的 NER 基因转录，从而抑制 DNA 修复。PHD抑制增强了NER基因的转录并促进了CEdG修复。这些结果与高血糖在促进基因组不稳定性中的作用一致，作为增加代谢疾病癌症风险的潜在机制。由于许多 NER 基因在 DNA 修复之外的多效性功能，