Bowles Isobel E, Orellana Esteban A
Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Remsen Building Room 725, 66 College St, Hanover, NH 03755 USA.
Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Remsen Building Room 725, 66 College St, Hanover, NH 03755 USA; Dartmouth Cancer Center, Dartmouth College, Lebanon, NH 03756, USA.
J Mol Biol. 2025 Aug 15;437(16):169046. doi: 10.1016/j.jmb.2025.169046. Epub 2025 Mar 8.
The vast array of cellular ribonucleic acid (RNA) modifications hold a crucial role in regulating RNA stability, folding, localization, and the accuracy of translation. Numerous diseases have been associated with mutations found in genes of RNA-modifying enzymes that can lead to truncated or misfolded proteins incapable of modifying their RNA substrates, causing downstream defects. In contrast, dysregulated levels of RNA-modifying enzymes and the resulting changes in RNA modifications on their substrates are increasingly linked to the activation of oncogenic pathways. This phenomenon has been especially studied through the lens of methyltransferases such as METTL1 and METTL3. The field has developed several small molecule inhibitors of RNA-modifying enzymes to mitigate their related diseases, including targeting the upregulation of METTL3 in cancer. However, increasing evidence suggests that RNA-modifying enzymes play essential roles in numerous cellular processes, including the immune response, neural health, and regeneration, among others. This could lead to off-target effects when treating proteins with small molecules, particularly when these enzymes are upregulated. We propose that developing treatments to specifically target the RNA substrates mis-regulated due to abnormal levels of RNA-modifying enzymes responsible for malignant hallmarks may offer an alternative strategy for treating diseases. We review current RNA-targeted therapies and the diseases they target, including advancements in oligonucleotide modalities and small molecules. We also identify gaps in knowledge that need to be addressed to enhance drug development in the epitranscriptome field to use these therapies to target mis-regulated RNA stemming from altered RNA-modifying enzyme levels.
种类繁多的细胞核糖核酸（RNA）修饰在调节RNA稳定性、折叠、定位及翻译准确性方面发挥着关键作用。许多疾病都与RNA修饰酶基因中的突变有关，这些突变可导致截短或错误折叠的蛋白质无法修饰其RNA底物，从而引起下游缺陷。相比之下，RNA修饰酶水平失调及其底物上RNA修饰的相应变化与致癌途径的激活越来越相关。这一现象尤其通过诸如METTL1和METTL3等甲基转移酶得到了研究。该领域已开发出几种RNA修饰酶的小分子抑制剂来减轻与其相关的疾病，包括针对癌症中METTL3的上调。然而，越来越多的证据表明，RNA修饰酶在包括免疫反应、神经健康和再生等众多细胞过程中发挥着重要作用。在用小分子治疗蛋白质时，这可能会导致脱靶效应，尤其是当这些酶上调时。我们提出，开发专门针对因负责恶性特征的RNA修饰酶水平异常而失调的RNA底物的治疗方法，可能为治疗疾病提供一种替代策略。我们综述了当前的RNA靶向疗法及其所针对的疾病，包括寡核苷酸形式和小分子方面的进展。我们还确定了知识上的差距，这些差距需要加以解决，以加强表观转录组领域的药物开发，从而利用这些疗法靶向由RNA修饰酶水平改变引起的失调RNA。
