Chemical modifications of human ribosomal RNA (rRNA) are introduced during biogenesis and have been implicated in the dysregulation of protein synthesis, as is found in cancer and other diseases. However, their role in this phenomenon is unknown. Here we visualize more than 130 individual rRNA modifications in the three-dimensional structure of the human ribosome, explaining their structural and functional roles. In addition to a small number of universally conserved sites, we identify many eukaryote- or human-specific modifications and unique sites that form an extended shell in comparison to bacterial ribosomes, and which stabilize the RNA. Several of the modifications are associated with the binding sites of three ribosome-targeting antibiotics, or are associated with degenerate states in cancer, such as keto alkylations on nucleotide bases reminiscent of specialized ribosomes. This high-resolution structure of the human 80S ribosome paves the way towards understanding the role of epigenetic rRNA modifications in human diseases and suggests new possibilities for designing selective inhibitors and therapeutic drugs.

中文翻译：

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人类 80S 核糖体结构中化学修饰的可视化

人类核糖体 RNA (rRNA) 的化学修饰是在生物发生过程中引入的，并且与蛋白质合成的失调有关，如在癌症和其他疾病中发现的那样。然而，它们在这种现象中的作用是未知的。在这里，我们在人类核糖体的三维结构中可视化了 130 多个单独的 rRNA 修饰，解释了它们的结构和功能作用。除了少数普遍保守的位点外，我们还确定了许多真核生物或人类特异性修饰和独特位点，与细菌核糖体相比，它们形成了扩展外壳，并稳定了 RNA。其中一些修饰与三种核糖体靶向抗生素的结合位点有关，或者与癌症的退化状态有关，例如核苷酸碱基上的酮烷基化，让人想起专门的核糖体。人类 80S 核糖体的这种高分辨率结构为了解表观遗传 r​​RNA 修饰在人类疾病中的作用铺平了道路，并为设计选择性抑制剂和治疗药物提供了新的可能性。