刺激诱导的 RNA 动态结构重塑维持细胞生理功能和生存的机制仍不清楚。在这里，我们发现在 MGMT 启动子甲基化胶质母细胞瘤 (GBM) 中，RNA 解旋酶 DEAD-box 解旋酶 46 (DDX46) 被替莫唑胺 (TMZ) 激活的检查点激酶 1 (CHK1) 磷酸化，导致从致密到松散的结构构象变化和 DDX46 解旋酶活性增加。 DDX46 介导的 LINC01956 三级结构重塑将 LINC01956 的结合基序暴露于 O6-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 的 3' 非翻译区。这加速了 MGMT mRNA 向 RNA 输出机制的募集以及 MGMT mRNA 从细胞核到细胞质的运输，导致 MGMT 丰度和 TMZ 耐药性增加。使用患者来源的异种移植物（PDX）和肿瘤类器官模型，我们发现CHK1抑制剂SRA737治疗消除了TMZ诱导的LINC01956结构重塑和随后的MGMT上调，使TMZ耐药的MGMT启动子甲基化GBM对TMZ重新敏感。总之，这些发现强调了替莫唑胺诱导 RNA 结构重塑的机制，并可能代表 TMZ 耐药 MGMT 启动子甲基化 GBM 患者的潜在治疗策略。

The mechanisms underlying stimuli-induced dynamic structural remodeling of RNAs for the maintenance of cellular physiological function and survival remain unclear. Here, we showed that in MGMT promoter-methylated glioblastoma (GBM), the RNA helicase DEAD-box helicase 46 (DDX46) is phosphorylated by temozolomide (TMZ)-activated checkpoint kinase 1 (CHK1), resulting in a dense-to-loose conformational change and an increase in DDX46 helicase activity. DDX46-mediated tertiary structural remodeling of LINC01956 exposes the binding motifs of LINC01956 to the 3' untranslated region of O6-methylguanine DNA methyltransferase (MGMT). This accelerates recruitment of MGMT mRNA to the RNA export machinery and transportation of MGMT mRNA from the nucleus to the cytoplasm, leading to increased MGMT abundance and TMZ resistance. Using patient-derived xenograft (PDX) and tumor organoid models, we found that treatment with the CHK1 inhibitor SRA737abolishes TMZ-induced structural remodeling of LINC01956 and subsequent MGMT up-regulation, resensitizing TMZ-resistant MGMT promoter-methylated GBM to TMZ. In conclusion, these findings highlight a mechanism underlying temozolomide-induced RNA structural remodeling and may represent a potential therapeutic strategy for patients with TMZ-resistant MGMT promoter-methylated GBM.