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 O 6 -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.

中文翻译：

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LINC01956 的动态结构重塑增强了 MGMT 甲基化胶质母细胞瘤的替莫唑胺耐药性


刺激诱导的 RNA 动态结构重塑以维持细胞生理功能和存活的机制仍不清楚。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，导致密集到松散的构象变化和 DDX46 解旋酶活性增加。DDX46 介导的 LINC01956 的三级结构重塑将 LINC01956 的结合基序暴露于 O 6-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，我们发现用 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 MGMT 启动子甲基化 GBM 对 TMZ 重新敏感。总之，这些发现突出了替莫唑胺诱导的 RNA 结构重塑的潜在机制，可能代表了 TMZ 耐药 MGMT 启动子甲基化 GBM 患者的潜在治疗策略。