Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22903, USA.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77550, USA.
Nucleic Acids Res. 2024 Aug 12;52(14):8534-8551. doi: 10.1093/nar/gkae431.
DExD-box RNA proteins DDX39A and DDX39B are highly homologous paralogs that are conserved in vertebrates. They are required for energy-driven reactions involved in RNA processing. Although we have some understanding of how their functions overlap in RNA nuclear export, our knowledge of whether or not these proteins have specific or redundant functions in RNA splicing is limited. Our previous work has shown that DDX39B is responsible for regulating the splicing of important immune transcripts IL7R and FOXP3. In this study, we aimed to investigate whether DDX39A, a highly homologous paralog of DDX39B, plays a similar role in regulating alternative RNA splicing. We find that DDX39A and DDX39B have significant redundancy in their gene targets, but there are targets that uniquely require one or the other paralog. For instance, DDX39A is incapable of complementing defective splicing of IL7R exon 6 when DDX39B is depleted. This exon and other cassette exons that specifically depend on DDX39B have U-poor/C-rich polypyrimidine tracts in the upstream intron and this variant polypyrimidine tract is required for DDX39B dependency. This study provides evidence that despite a high degree of functional redundancy, DDX39A and DDX39B are selectively required for the splicing of specific pre-mRNAs.
DExD-box RNA 蛋白 DDX39A 和 DDX39B 是高度同源的并系同源物，在脊椎动物中保守。它们是涉及 RNA 加工的能量驱动反应所必需的。尽管我们对它们在 RNA 核输出中的功能重叠有了一些了解，但我们对这些蛋白质在 RNA 剪接中是否具有特定或冗余功能的了解有限。我们之前的工作表明，DDX39B 负责调节重要免疫转录物 IL7R 和 FOXP3 的剪接。在这项研究中，我们旨在研究 DDX39B 的高度同源并系同源物 DDX39A 是否在调节选择性 RNA 剪接中发挥类似作用。我们发现 DDX39A 和 DDX39B 在其基因靶标中具有显著的冗余性，但也有一些靶标需要一个或另一个并系同源物。例如，当 DDX39B 耗尽时，DDX39A 无法弥补 IL7R 外显子 6 的缺陷剪接。该外显子和其他特定依赖 DDX39B 的盒式外显子在上游内含子中具有 U 贫乏/C 丰富的聚嘧啶序列，这种变体聚嘧啶序列是 DDX39B 依赖性所必需的。这项研究提供了证据表明，尽管具有高度的功能冗余性，但 DDX39A 和 DDX39B 仍然是特定前体 mRNA 剪接所必需的。
