Rhabdoid tumors, characterized and driven by the loss of the mammalian SWItch/sucrose nonfermentable subunit SMARCB1, are very aggressive childhood cancers that can arise in the brain, the kidney, or soft tissues. Cell lines derived from these tumors are specifically sensitivity to the translation inhibitor homoharringtonine. Having recently demonstrated mammalian SWItch/sucrose nonfermentable roles in translation, we assessed SMARCB1 potential roles in translation in rhabdoid tumor cells. We first revealed by cell viability assays that rhabdoid tumor cells’ sensitivity to homoharringtonine were dependent on the absence of SMARCB1. Polysome profiling and immunoprecipitation experiments demonstrated the interaction of SMARCB1 with translation machinery. Global translation assays and ribosome profiling experiments further revealed that SMARCB1 re-expression increased global translation and altered translation efficiency of specific mRNAs. Most regulated mRNAs presented an increased translation efficiency and were involved in differentiation. In comparison with the entire transcriptome, these mRNAs presented a longer coding sequence and were enriched in GC. Finally, we demonstrated that SMARCB1 re-expression increased cytoplasmic localization of these mRNAs and that gene encoding these transcripts were bound by SMARCA4 and SMARCC1. In conclusion, this study reveals that the loss of SMARCB1 in rhabdoid tumors has specific consequences on mRNAs translation with potential to unveil new dependencies.

中文翻译：

---

横纹肌样瘤细胞中 SMARCB1 的缺失增加了对翻译抑制的敏感性，并改变了特异性 mRNA 的翻译效率


横纹肌样瘤的特征和驱动因素是哺乳动物 SWItch/蔗糖不可发酵亚基SMARCB1的缺失，是可能起源于大脑、肾脏或软组织的极具侵袭性的儿童癌症。源自这些肿瘤的细胞系对翻译抑制剂高三尖平调碱特别敏感。最近证明了哺乳动物 SWItch/蔗糖不可发酵在翻译中的作用，我们评估了SMARCB1在横纹肌样肿瘤细胞翻译中的潜在作用。我们首先通过细胞活力测定揭示了横纹肌样肿瘤细胞对高三尖杉木碱的敏感性取决于是否存在SMARCB1。多核糖体分析和免疫沉淀实验证明了 SMARCB1 与翻译机制的相互作用。全局翻译分析和核糖体分析实验进一步揭示，SMARCB1 再表达增加了特定 mRNA 的全局翻译并改变了翻译效率。大多数受调节的 mRNAs 表现出更高的翻译效率并参与分化。与整个转录组相比，这些 mRNA 呈现更长的编码序列并在 GC 中富集。最后，我们证明SMARCB1再表达增加了这些 mRNA 的细胞质定位，并且编码这些转录本的基因被 SMARCA4 和 SMARCC1 结合。总之，本研究揭示了横纹肌样瘤中 SMARCB1 的缺失对 mRNA 翻译有特定影响，有可能揭示新的依赖性。