PDF(Pubmed)
Abstract：
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.
The removal of introns and the joining of exons into mature mRNA by the spliceosome is crucial in regulating gene expression, simultaneously safeguarding genome integrity and enhancing proteome diversity in multicellular organisms. Spliceosome dysfunction is thus associated with various diseases and organismal aging. Our study describes the cascade of events in response to spliceosome dysfunction. We identified two transcription factors as drivers of a stress response program triggered by spliceosome dysfunction, which dramatically remodel gene expression to protect tissue integrity and induce a senescent-like state in damaged cells prior to their inevitable elimination. Together, we highlight the indispensable role of spliceosomes in maintaining homeostasis and implicate spliceosome dysfunction in senescent cell accumulation associated with the pathomechanisms of spliceopathies and aging.
The removal of introns and the joining of exons into mature mRNA by the spliceosome is crucial in regulating gene expression, simultaneously safeguarding genome integrity and enhancing proteome diversity in multicellular organisms. Spliceosome dysfunction is thus associated with various diseases and organismal aging. Our study describes the cascade of events in response to spliceosome dysfunction. We identified two transcription factors as drivers of a stress response program triggered by spliceosome dysfunction, which dramatically remodel gene expression to protect tissue integrity and induce a senescent-like state in damaged cells prior to their inevitable elimination. Together, we highlight the indispensable role of spliceosomes in maintaining homeostasis and implicate spliceosome dysfunction in senescent cell accumulation associated with the pathomechanisms of spliceopathies and aging.
摘要：
通过剪接体对新生前mRNA的共转录加工对于调节基因表达和维持基因组完整性至关重要。这里,我们表明，果蝇想象细胞中U5功能性小核核糖核蛋白颗粒（snRNPs）的缺乏导致广泛的转录组重塑和高度诱变R环的积累，引发强烈的应激反应和细胞周期停滞。尽管增殖能力受损，U5snRNP缺陷细胞增加了蛋白质翻译和细胞大小，在通过凋亡逐渐消除之前引起器官内生长失衡。我们确定Xrp1-Irbp18异二聚体是U5snRNP故障下游的转录和细胞应激程序的主要驱动因素。在U5snRNP缺陷细胞中敲除Xrp1或Irbp18减弱了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，减少Xrp1-Irbp18，没有挽救拼接缺陷，强调细胞和组织稳态的精确剪接的要求。我们的工作为剪接和DNA损伤反应之间的串扰提供了新的见解，并将Xrp1-Irbp18异二聚体定义为剪接体故障的关键传感器和应激诱导的细胞衰老程序的介体。
内含子的去除和外显子通过剪接体连接到成熟的mRNA中对于调节基因表达至关重要。同时维护多细胞生物的基因组完整性和增强蛋白质组多样性。因此，剪接体功能障碍与各种疾病和机体衰老有关。我们的研究描述了响应剪接体功能障碍的事件级联。我们确定了两个转录因子作为由剪接体功能障碍触发的应激反应程序的驱动因素，这极大地重塑基因表达以保护组织完整性，并在不可避免的消除之前在受损细胞中诱导衰老样状态。一起,我们强调了剪接体在维持体内平衡中不可或缺的作用，并暗示剪接体功能障碍在与剪接病和衰老的病理机制相关的衰老细胞积累中。
内含子的去除和外显子通过剪接体连接到成熟的mRNA中对于调节基因表达至关重要。同时维护多细胞生物的基因组完整性和增强蛋白质组多样性。因此，剪接体功能障碍与各种疾病和机体衰老有关。我们的研究描述了响应剪接体功能障碍的事件级联。我们确定了两个转录因子作为由剪接体功能障碍触发的应激反应程序的驱动因素，这极大地重塑基因表达以保护组织完整性，并在不可避免的消除之前在受损细胞中诱导衰老样状态。一起,我们强调了剪接体在维持体内平衡中不可或缺的作用，并暗示剪接体功能障碍在与剪接病和衰老的病理机制相关的衰老细胞积累中。
