Oncogenic mutations in the RNA splicing factors SRSF2, SF3B1, and U2AF1 are the most frequent class of mutations in myelodysplastic syndromes and are also common in clonal hematopoiesis, acute myeloid leukemia, chronic lymphocytic leukemia, and a variety of solid tumors. They cause genome-wide splicing alterations that affect important regulators of hematopoiesis. Several mRNA isoforms promoted by the various splicing factor mutants comprise a premature termination codon (PTC) and are therefore potential targets of nonsense-mediated mRNA decay (NMD). In light of the mechanistic relationship between splicing and NMD, we sought evidence for a specific role of mutant SRSF2 in NMD. We show that SRSF2 Pro95 hot spot mutations elicit enhanced mRNA decay, which is dependent on sequence-specific RNA binding and splicing. SRSF2 mutants enhance the deposition of exon junction complexes (EJCs) downstream from the PTC through RNA-mediated molecular interactions. This architecture then favors the association of key NMD factors to elicit mRNA decay. Gene-specific blocking of EJC deposition by antisense oligonucleotides circumvents aberrant NMD promoted by mutant SRSF2, restoring the expression of PTC-containing transcript. Our study uncovered critical effects of SRSF2 mutants in hematologic malignancies, reflecting the regulation at multiple levels of RNA metabolism, from splicing to decay.

中文翻译：

---

MDS中反复出现的SRSF2突变会影响剪接和NMD。

RNA剪接因子SRSF2，SF3B1和U2AF1中的致癌突变是骨髓增生异常综合症中最常见的突变类型，并且在克隆性造血，急性髓细胞性白血病，慢性淋巴细胞性白血病和各种实体瘤中也很常见。它们引起全基因组剪接改变，影响造血作用的重要调节剂。由各种剪接因子突变体促进的几种mRNA同工型包含一个过早终止密码子（PTC），因此是无义介导的mRNA衰变（NMD）的潜在靶标。鉴于剪接和NMD之间的机制关系，我们寻求证据证明SRSF2突变体在NMD中具有特定作用。我们显示SRSF2 Pro95热点突变引起增强的mRNA衰减，这取决于序列特异性RNA结合和剪接。SRSF2突变体通过RNA介导的分子相互作用增强了PTC下游的外显子连接复合物（EJC）的沉积。然后，该体系结构有利于关键NMD因子的关联以引起mRNA衰减。反义寡核苷酸对EJC沉积的基因特异性阻断可避免突变SRSF2促进的异常NMD，从而恢复含PTC转录物的表达。我们的研究发现了SRSF2突变体在血液系统恶性肿瘤中的关键作用，反映了从剪接到衰变的多个RNA代谢水平的调控。反义寡核苷酸对EJC沉积的基因特异性阻断可避免突变SRSF2促进的异常NMD，从而恢复含PTC转录物的表达。我们的研究发现了SRSF2突变体在血液系统恶性肿瘤中的关键作用，反映了从剪接到衰变的多个RNA代谢水平的调控。反义寡核苷酸对EJC沉积的基因特异性阻断可避免突变SRSF2促进的异常NMD，从而恢复含PTC转录物的表达。我们的研究发现了SRSF2突变体在血液系统恶性肿瘤中的关键作用，反映了从剪接到衰变的多个RNA代谢水平的调控。