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SRRM2 organizes splicing condensates to regulate alternative splicing
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2022-08-05 , DOI: 10.1093/nar/gkac669
Shaohai Xu 1 , Soak-Kuan Lai 1 , Donald Yuhui Sim 1 , Warren Shou Leong Ang 1 , Hoi Yeung Li 1 , Xavier Roca 1
Affiliation  

SRRM2 is a nuclear-speckle marker containing multiple disordered domains, whose dysfunction is associated with several human diseases. Using mainly EGFP-SRRM2 knock-in HEK293T cells, we show that SRRM2 forms biomolecular condensates satisfying most hallmarks of liquid-liquid phase separation, including spherical shape, dynamic rearrangement, coalescence and concentration dependence supported by in vitro experiments. Live-cell imaging shows that SRRM2 organizes nuclear speckles along the cell cycle. As bona-fide splicing factor present in spliceosome structures, SRRM2 deficiency induces skipping of cassette exons with short introns and weak splice sites, tending to change large protein domains. In THP-1 myeloid-like cells, SRRM2 depletion compromises cell viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 induces a FES splice isoform that attenuates innate inflammatory responses, and MUC1 isoforms that undergo shedding with oncogenic properties. We conclude that SRRM2 acts as a scaffold to organize nuclear speckles, regulating alternative splicing in innate immunity and cell homeostasis.

中文翻译:

SRRM2 组织剪接冷凝物来调节选择性剪接

SRRM2 是一种包含多个无序结构域的核斑点标记,其功能障碍与多种人类疾病有关。我们主要使用 EGFP-SRRM2 敲入 HEK293T 细胞,表明 SRRM2 形成的生物分子凝聚物满足液-液相分离的大多数特征,包括体外实验支持的球形、动态重排、聚结和浓度依赖性。活细胞成像显示 SRRM2 沿着细胞周期组织核斑点。作为存在于剪接体结构中的真正剪接因子,SRRM2 缺乏会导致具有短内含子和弱剪接位点的盒式外显子跳过,倾向于改变大的蛋白质结构域。在 THP-1 髓样细胞中,SRRM2 消耗会损害细胞活力,上调分化标志物,并使细胞对抗白血病药物敏感。SRRM2 诱导一种 FES 剪接同种型,可减弱先天性炎症反应,而 MUC1 同种型则经历具有致癌特性的脱落。我们得出结论,SRRM2 作为组织核斑点的支架,调节先天免疫和细胞稳态中的选择性剪接。
更新日期:2022-08-05
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