State Key Laboratory of Bioelectronics, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Int J Mol Sci. 2021 May 8;22(9):5008. doi: 10.3390/ijms22095008.
Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.
核苷酸切除修复 (NER) 可解决 DNA 加合物，如紫外线引起的加合物。NER 缺陷 (dNER) 会导致更高的突变率，从而导致癌症发展和早衰表型。在这里，我们使用同基因 dNER 模型细胞系建立了一个基因表达特征，可以准确预测细胞系和患者样本中功能性 NER 能力。至关重要的是，没有一个鉴定出的 NER 缺陷细胞系在任何 NER 基因中存在突变，这表明 NER 缺陷的流行率可能目前被低估了。鉴定出能诱导 dNER 基因表达特征的化合物导致发现 GSK3 抑制可使 NER 功能受损，与顺铂联合治疗时会产生协同作用。此外，我们使用 dNER 基因特征作为药物发现平台，预测并验证了多种与 NER 缺陷具有合成致死性的新型药物。总之，我们的工作提供了一个 NER 功能的动态预测指标，可用于治疗分层以及开发人类肿瘤中的新生物学见解。
