School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
EMBO J. 2022 Mar 15;41(6):e108544. doi: 10.15252/embj.2021108544. Epub 2021 Dec 1.
Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA-binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA-modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'-O-methylation of tRNAs, thus regulating translation in a manner depending on its tRNA-modification activity. On the other hand, nucleus-localized hTrmt13 directly binds DNA as a transcriptional co-activator of key epithelial-mesenchymal transition factors, thereby promoting cell migration independent of tRNA-modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA-modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.
由于许多 RNA 和 RBPs 普遍定位于活性染色质区域，许多 RNA 结合蛋白 (RBP) 可能是潜在的转录调节剂。通常认为 RBP 通过非编码 RNA 来调节转录。在这里，我们描述了先前未表征的 tRNA 修饰酶 hTrmt13 通过一种独特的、双重机制进行转录调控。一方面，hTrmt13 在细胞质中发挥作用，催化 tRNA 的 2'-O-甲基化，从而以依赖其 tRNA 修饰活性的方式调节翻译。另一方面，核定位的 hTrmt13 作为关键上皮-间充质转化因子的转录共激活因子直接结合 DNA，从而独立于 tRNA 修饰活性促进细胞迁移。hTrmt13 的这两种功能是相互排斥的，因为它可以通过其 CHHC 锌指结构域结合 DNA 或 tRNA。最后，我们发现 hTrmt13 的表达与不同癌症患者的不良预后和生存密切相关。我们发现 RNA 修饰酶的非催化作用为理解表观转录组调控提供了新的视角。
