Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
Nucleic Acids Res. 2024 Mar 21;52(5):2093-2111. doi: 10.1093/nar/gkae055.
Co-transcriptional processing of nascent pre-mRNAs by the spliceosome is vital to regulating gene expression and maintaining genome integrity. Here, we show that the deficiency of functional U5 small nuclear ribonucleoprotein particles (snRNPs) in Drosophila imaginal cells causes extensive transcriptome remodeling and accumulation of highly mutagenic R-loops, triggering a robust stress response and cell cycle arrest. Despite compromised proliferative capacity, the U5 snRNP-deficient cells increased protein translation and cell size, causing intra-organ growth disbalance before being gradually eliminated via apoptosis. We identify the Xrp1-Irbp18 heterodimer as the primary driver of transcriptional and cellular stress program downstream of U5 snRNP malfunction. Knockdown of Xrp1 or Irbp18 in U5 snRNP-deficient cells attenuated JNK and p53 activity, restored normal cell cycle progression and growth, and inhibited cell death. Reducing Xrp1-Irbp18, however, did not rescue the splicing defects, highlighting the requirement of accurate splicing for cellular and tissue homeostasis. Our work provides novel insights into the crosstalk between splicing and the DNA damage response and defines the Xrp1-Irbp18 heterodimer as a critical sensor of spliceosome malfunction and mediator of the stress-induced cellular senescence program.
新生前体 mRNA 的共转录加工由剪接体完成，这对调节基因表达和维持基因组完整性至关重要。在这里，我们表明，果蝇 imaginal 细胞中功能性 U5 小核核糖核蛋白颗粒 (snRNP) 的缺乏会导致广泛的转录组重排和高度诱变的 R-环积累，从而引发强烈的应激反应和细胞周期停滞。尽管增殖能力受损，U5 snRNP 缺陷细胞增加了蛋白质翻译和细胞大小，导致器官内生长失衡，然后通过细胞凋亡逐渐被淘汰。我们确定 Xrp1-Irbp18 异二聚体是 U5 snRNP 功能障碍下游转录和细胞应激程序的主要驱动因素。在 U5 snRNP 缺陷细胞中敲低 Xrp1 或 Irbp18 可减弱 JNK 和 p53 活性，恢复正常的细胞周期进程和生长，并抑制细胞死亡。然而，降低 Xrp1-Irbp18 并不能挽救剪接缺陷，这突出了准确剪接对于细胞和组织稳态的必要性。我们的工作为剪接和 DNA 损伤反应之间的相互作用提供了新的见解，并将 Xrp1-Irbp18 异二聚体定义为剪接体功能障碍的关键传感器和应激诱导的细胞衰老程序的介质。
