Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
Department of Biochemistry, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.
Mol Cell. 2020 Mar 5;77(5):1014-1031.e13. doi: 10.1016/j.molcel.2020.01.001. Epub 2020 Feb 3.
The La-related protein 7 (LARP7) forms a complex with the nuclear 7SK RNA to regulate RNA polymerase II transcription. It has been implicated in cancer and the Alazami syndrome, a severe developmental disorder. Here, we report a so far unknown role of this protein in RNA modification. We show that LARP7 physically connects the spliceosomal U6 small nuclear RNA (snRNA) with a distinct subset of box C/D small nucleolar RNAs (snoRNAs) guiding U6 2'-O-methylation. Consistently, these modifications are severely compromised in the absence of LARP7. Although general splicing remains largely unaffected, transcriptome-wide analysis revealed perturbations in alternative splicing in LARP7-depleted cells. Importantly, we identified defects in 2'-O-methylation of the U6 snRNA in Alazami syndrome siblings carrying a LARP7 mutation. Our data identify LARP7 as a bridging factor for snoRNA-guided modification of the U6 snRNA and suggest that alterations in splicing fidelity contribute to the etiology of the Alazami syndrome.
La 相关蛋白 7（LARP7）与核 7SK RNA 形成复合物，调节 RNA 聚合酶 II 转录。它与癌症和 Alazami 综合征有关，后者是一种严重的发育障碍。在这里，我们报告了该蛋白在 RNA 修饰中一个迄今为止未知的作用。我们表明，LARP7 使剪接体 U6 小核 RNA（snRNA）与引导 U6 2'-O-甲基化的特定盒 C/D 小核仁 RNA（snoRNA）发生物理连接。一致地，在缺乏 LARP7 的情况下，这些修饰严重受损。尽管一般剪接基本不受影响，但全转录组分析显示 LARP7 耗尽细胞中的可变剪接受到干扰。重要的是，我们在携带 LARP7 突变的 Alazami 综合征兄弟姐妹中发现 U6 snRNA 2'-O-甲基化缺陷。我们的数据将 LARP7 鉴定为 snoRNA 指导的 U6 snRNA 修饰的桥接因子，并表明剪接保真度的改变可能导致 Alazami 综合征的发生。
