文章：

RNA剪接因子作为肿瘤蛋白和肿瘤抑制因子

RNA splicing factors as oncoproteins and tumour suppressors

原文发布日期：2016-06-10

DOI: 10.1038/nrc.2016.51

类型: Review Article

开放获取: 否

要点：

1. Genetic and functional data indicate that RNA splicing factors can act as oncoproteins as well as tumour suppressors.
2. A subset of RNA splicing factors are recurrent targets of specific point mutations in cancer. Many other splicing factors exhibit dysregulated expression in cancer.
3. In many cases, recurrent spliceosomal mutations alter splice site or exon recognition preferences to cause abnormal RNA splicing.
4. Spliceosomal mutations are sufficient to impair myeloid differentiation in mouse models. In the case of serine/arginine-rich splicing factor 2 (SRSF2), impaired differentiation has been linked to a specific splicing change in a downstream gene (enhancer of zeste homologue 2 (EZH2)).
5. Spliceosomal mutations may affect cellular processes, including epigenetic regulation, the DNA damage response and nonsense-mediated decay, in addition to regulation of RNA splicing.
6. Small molecules that disrupt splicing catalysis and/or targeted correction of specific splicing changes may provide novel therapeutic opportunities for cancers bearing spliceosomal mutations.

要点翻译：

1. 遗传学和功能数据表明，RNA剪接因子既可充当癌蛋白也可作为肿瘤抑制因子。
2. 一部分RNA剪接因子在癌症中成为特定点突变的反复靶标。许多其他剪接因子在癌症中表现出表达失调。
3. 多数情况下，复发性剪接体突变会改变剪接位点或外显子识别偏好，导致RNA剪接异常。
4. 剪接体突变足以损害小鼠模型中的髓系分化。以丝氨酸/精氨酸富集剪接因子2（SRSF2）为例，其分化受损与下游基因（zeste同源物2增强子EZH2）的特异性剪接改变相关。
5. 除RNA剪接调控外，剪接体突变还可能影响包括表观遗传调控、DNA损伤反应和无义介导的mRNA降解在内的细胞过程。
6. 干扰剪接催化的小分子药物和/或特异性剪接改变的靶向校正，可能为携带剪接体突变的癌症提供新的治疗机遇。

英文摘要：

The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these 'spliceosomal mutations' suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic and biological effects of spliceosomal mutations are crucial for the development of cancer therapies targeted at these mutations.

摘要翻译： 

近期对癌症进行的基因组学特征分析发现，存在反复出现的体细胞点突变和拷贝数变化，这些变化影响了编码RNA剪接因子的基因。最初对这些“剪接体突变”的研究表明，与野生型对应物相比，携带这些突变的蛋白质表现出不同的剪接位点和/或外显子识别偏好，从而导致癌症特异性的剪接错误。剪接机制的这种变化可能在癌细胞中产生新的脆弱点，可以通过使用能够影响剪接过程的化合物来加以治疗利用。进一步研究剪接体突变的生化、基因组和生物学效应，对于开发针对这些突变的癌症疗法至关重要。

原文链接：

RNA splicing factors as oncoproteins and tumour suppressors