Queuosine 修饰依赖的组氨酸 tRNA 片段促进细胞类型依赖的增殖
Queuosine-modification dependent histidyl tRNA fragment promotes cell-type dependent proliferation
在 MCF7 乳腺癌细胞系中，Queuosine（Q）修饰的 tRNA 经 QTRT1/2 修饰酶复合体作用后抑制细胞增殖，而 Q 修饰依赖的 tRFHis 转染则促进增殖、敲低内源 tRFHis 则降低增殖。多聚核糖体谱分析显示核糖体蛋白翻译效率下降，与 Q 依赖的增殖抑制一致。用 tRFHis 对 MCF7 裂解液做蛋白 pull-down，鉴定出 Musashi RNA 结合蛋白 2（Msi2）为 tRFHis 结合蛋白；敲低 Msi2 减弱了 Q 修饰依赖或 tRFHis 依赖的增殖效应。
来源：Nucleic Acids Research · doi.org
tRNA fragments (tRFs) are natural, small non-coding RNAs produced by endogenous ribonucleolytic cleavage of tRNAs. tRFs play a role in many biological pathways, including regulation of cell proliferation. Specific tRNA modifications affect tRF biogenesis. Queuosine (Q) modification occurs at the wobble anticodon nucleotide of 4 mammalian tRNAs and protects these tRNAs from fragmentation. Here, we investigated cell-type and tRNA Q-modification dependencies on mammalian cell proliferation. We found that Q-modified tRNA can either increase, decrease, or make no difference in proliferation. Proliferation decreased in MCF7, a breast cancer cell line, when tRNAs were Q-modified and dependent on the modification enzyme complex, QTRT1/2. MCF7 proliferation increases upon the transfection of Q-modification-dependent tRFHis or decreases upon knockdown of endogenous tRFHis. Consistent with Q-dependent proliferation reduction, polysome profiling showed decreased translation efficiency of ribosomal proteins. Finally, protein pull-down of MCF7 lysates using tRFHis identified Musashi RNA-binding protein 2 (Msi2) as a tRFHis-binding protein. Msi2 knockdown reduced the Q-modification-dependent or tRFHis dependent cell proliferation effect. Our results illustrate a highly cell-type-dependent proliferation effect of tRNA Q-modification, suggesting multi-faceted mechanisms in studying this ubiquitous tRNA modification.