Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Nucleic Acids Res. 2022 Nov 28;50(21):12400-12424. doi: 10.1093/nar/gkac659.
Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5'-monomethylguanosine cap of small nuclear RNAs (snRNAs) to a trimethylguanosine cap. Here, we show that loss of TGS1 in Caenorhabditis elegans, Drosophila melanogaster and Danio rerio results in neurological phenotypes similar to those caused by survival motor neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3' tails that are often uridylated. snRNAs with defective 3' terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.
三甲基鸟苷合酶 1（TGS1）是一种高度保守的酶，可将小核 RNA（snRNA）的 5'-单甲基鸟苷帽转化为三甲基鸟苷帽。在这里，我们表明，秀丽隐杆线虫、黑腹果蝇和斑马鱼中 TGS1 的缺失会导致与运动神经元存活（SMN）缺乏引起的类似神经表型。重要的是，人 TGS1 的表达可改善果蝇和蠕虫中 SMN 依赖性的神经表型，表明 TGS1 可以部分抵消 SMN 缺乏的影响。HeLa 细胞中 TGS1 的缺失导致不成熟的 U2 和 U4atac snRNA 积累，其 3'末端较长，通常被尿嘧啶化。3'末端有缺陷的 snRNA 也在果蝇 Tgs1 突变体中积累。与 snRNA 成熟缺陷一致，TGS1 和 SMN 突变细胞还表现出部分重叠的转录组改变，包括异常剪接和通读转录本。总之，这些结果确定了 TGS1 的神经保护功能，并强化了 snRNA 成熟缺陷影响神经元存活和功能的观点。
