SRSF7 is an essential RNA-binding protein whose misexpression promotes cancer. Here, we describe how SRSF7 maintains its protein homeostasis in murine P19 cells using an intricate negative feedback mechanism. SRSF7 binding to its premessenger RNA promotes inclusion of a poison cassette exon and transcript degradation via nonsense-mediated decay (NMD). However, elevated SRSF7 levels inhibit NMD and promote translation of two protein halves, termed Split-ORFs, from the bicistronic SRSF7-PCE transcript. The first half acts as dominant-negative isoform suppressing poison cassette exon inclusion and instead promoting the retention of flanking introns containing repeated SRSF7 binding sites. Massive SRSF7 binding to these sites and its oligomerization promote the assembly of large nuclear bodies, which sequester SRSF7 transcripts at their transcription site, preventing their export and restoring normal SRSF7 protein levels. We further show that hundreds of human and mouse NMD targets, especially RNA-binding proteins, encode potential Split-ORFs, some of which are expressed under specific cellular conditions.

中文翻译：

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SRSF7通过Split-ORF的表达和核体装配来维持其体内平衡。

SRSF7是必需的RNA结合蛋白，其错误表达会促进癌症。在这里，我们描述了SRSF7如何使用复杂的负反馈机制在鼠P19细胞中维持其蛋白质稳态。SRSF7与其前信使RNA的结合促进无毒介导的外显子的包涵和转录产物通过无意义介导的衰变（NMD）的降解。但是，升高的SRSF7水平会抑制NMD并促进双顺反子SRSF7-PCE转录本中两个蛋白半段（称为Split-ORF）的翻译。前半部分充当显性阴性同种型，抑制毒物盒外显子包涵，并促进包含重复SRSF7结合位点的侧翼内含子的保留。大量SRSF7与这些位点的结合及其低聚作用促进了大型核体的组装，会在其转录位点隔离SRSF7转录物，从而阻止其输出并恢复正常的SRSF7蛋白水平。我们进一步表明，成百上千的人类和小鼠NMD目标，尤其是RNA结合蛋白，编码潜在的Split-ORF，其中一些在特定细胞条件下表达。