RBBP4 regulates the expression of the Mre11-Rad50-NBS1 (MRN) complex and promotes DNA double-strand break repair to mediate glioblastoma chemoradiotherapy resistance
RBBP4 regulates the expression of the Mre11-Rad50-NBS1 (MRN) complex and promotes DNA double-strand break repair to mediate glioblastoma chemoradiotherapy resistance
复制标题
RBBP4调节Mre11-Rad50-NBS1 (MRN)复合物的表达并促进DNA双链断裂修复以介导胶质母细胞瘤放化疗耐药
DOI：
10.1016/j.canlet.2023.216078
复制
发表时间：
2023-02-14
期刊：
影响因子：
9.7
通讯作者：
Lu, Yuntao
中科院分区：
文献类型：
--
作者：
Li, Junjie;Song, Chong;Lu, Yuntao
替莫唑胺（TMZ）和放疗（RT）治疗胶质母细胞瘤（GBM）主要通过诱导DNA双链断裂（DSB）（主要是通过无效的DNA错配修复（MMR））和诱导细胞凋亡来发挥抗肿瘤作用。在这里，我们提供的证据表明，RBBP 4通过招募转录因子和表观遗传调节因子来调节胶质母细胞瘤对化疗和放疗的抗性，这些转录因子和表观遗传调节因子与其启动子结合，以调节Mre 11-Rad 50-NBS 1（MRN）复合物的表达和DNA-DSB修复水平，这与U87 MG和LN 229胶质母细胞瘤细胞中TMZ和放疗诱导的DNA损伤的恢复密切相关，MGMT表达阴性。RBBP 4的破坏可诱导GBM细胞DNA损伤和细胞凋亡，以响应TMZ和放疗，并通过MGMT的独立途径增强放疗和化疗的敏感性。这些结果表明，在MGMT阴性GBM的化学-放射抗性的可能机制。此外，RBBP 4-MRN复合物调节轴可能为开发GBM的治疗敏感策略提供有趣的靶点。
For treatment of glioblastoma (GBM), temozolomide (TMZ) and radiotherapy (RT) exert antitumor effects by inducing DNA double-strand breaks (DSBs), mainly via futile DNA mismatch repair (MMR) and inducing apoptosis. Here, we provide evidence that RBBP4 modulates glioblastoma resistance to chemotherapy and radiotherapy by recruiting transcription factors and epigenetic regulators that bind to their promoters to regulate the expression of the Mre11-Rad50-NBS1(MRN) complex and the level of DNA-DSB repair, which are closely associated with recovery from TMZ-and radiotherapy-induced DNA damage in U87MG and LN229 glioblastoma cells, which have negative MGMT expression. Disruption of RBBP4 induced GBM cell DNA damage and apoptosis in response to TMZ and radiotherapy and enhanced radiotherapy and chemotherapy sensitivity by the inde-pendent pathway of MGMT. These results displayed a possible chemo-radioresistant mechanism in MGMT negative GBM. In addition, the RBBP4-MRN complex regulation axis may provide an interesting target for developing therapy-sensitizing strategies for GBM.