PDF(Pubmed)
Abstract：
Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated.
摘要：
无义介导的RNA衰变（NMD）降解携带过早终止密码子的转录本。NMD被认为可以防止有毒的截短蛋白质的合成。然而,NMD的丢失是否会导致截短蛋白的广泛产生尚不清楚.一种人类遗传病,面肩肱肌营养不良(FSHD),特征NMD在致病转录因子表达时急性抑制，DUX4.使用基于细胞的FSHD模型，我们显示了从生理NMD靶标产生截短的蛋白质，并发现RNA结合蛋白富含异常截短。一种RNA结合蛋白的NMD亚型，SRSF3，翻译产生稳定的截短的蛋白质，在FSHD患者来源的肌管中检测到。截短的SRSF3的异位表达赋予毒性，它的下调是细胞保护的。我们的结果描述了NMD损失的基因组规模影响。这种潜在有害的截短蛋白的广泛产生对FSHD生物学以及NMD被治疗性调节的其他遗传疾病具有影响。
