Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures.
Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures.
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DOI：
10.1016/j.tig.2017.03.001
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发表时间：
2017-05
期刊：
影响因子：
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通讯作者：
Kielkopf CL
中科院分区：
文献类型：
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作者：
Jenkins JL;Kielkopf CL
骨髓增生异常综合征（MDS）和相关恶性肿瘤患者中前体mRNA剪接因子的体细胞突变复发。尽管这些MDS相关突变改变了转录子的剪接，但这些单个氨基酸取代改变基因表达的机制仍然存在争议。剪接体中间体和相关蛋白复合物的新结构揭示了SF 3B1和U2AF 1前mRNA剪接因子的“热点”介导的分子相互作用。频繁突变的SF3B1残基接触前mRNA剪接位点。基于与其他剪接体亚基的结构同源性和最近发现的突变U2AF 1蛋白改变RNA结合，我们建议受影响的U2AF 1残基也接触前mRNA。改变的前体mRNA识别作为MDS相关的前体mRNA剪接因子突变中的分子主题出现。
Somatic mutations of pre-mRNA splicing factors recur among patients with myelodysplastic syndromes (MDS) and related malignancies. Although these MDS-relevant mutations alter splicing of a subset of transcripts, the mechanisms by which these single amino acid substitutions change gene expression remain controversial. New structures of spliceosome intermediates and associated protein complexes shed light on the molecular interactions mediated by “hotspots” of the SF3B1 and U2AF1 pre-mRNA splicing factors. The frequently mutated SF3B1 residues contact the pre-mRNA splice site. Based on structural-homology with other spliceosome subunits and recent findings of altered RNA binding by mutant U2AF1 proteins, we suggest that affected U2AF1 residues also contact pre-mRNA. Altered pre-mRNA recognition emerges as a molecular theme among MDS-relevant mutations of pre-mRNA splicing factors.