治疗恶性胶质母细胞瘤（GBM）的替莫唑胺（TMZ）和放射治疗（RT）通过诱导 DNA 双链断裂（DSBs），主要通过无谓 DNA 不匹配修复（MMR）和诱导细胞凋亡发挥抗肿瘤效应。在这里，我们提供证据表明 RBBP4 通过招募转录因子和表观遗传调节剂来结合它们的启动子，调控 Mre11-Rad50-NBS1（MRN）复合物的表达水平和 DNA-DSB 修复水平，这些与在具有负 MGMT 表达的 U87MG 和 LN229 胶质母细胞瘤细胞中从 TMZ 和放射治疗诱导的 DNA 损伤中恢复密切相关。破坏 RBBP4 通过 MGMT 的独立途径引起 GBM 细胞 DNA 损伤和细胞凋亡，增强了放射治疗和化疗的敏感性。这些结果显示了 MGMT 阴性 GBM 中可能存在的一种化疗和放射治疗耐药机制。此外，RBBP4-MRN 复合物调节轴可能为开发 GBM 治疗敏感战略提供一个有趣的靶标。版权所有©2023 Elsevier B.V.。保留所有权利。

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 independent 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.Copyright © 2023 Elsevier B.V. All rights reserved.