Acquired point mutations of pre-mRNA splicing factors recur among cancers, leukemias, and related neoplasms. Several studies have established that somatic mutations of a U2AF1 subunit, which normally recognizes 3′ splice site junctions, recur among myelodysplastic syndromes. The U2AF2 splicing factor recognizes polypyrimidine signals that precede most 3′ splice sites as a heterodimer with U2AF1. In contrast with those of the well-studied U2AF1 subunit, descriptions of cancer-relevant U2AF2 mutations and their structural relationships are lacking. Here, we survey databases of cancer-associated mutations and identify recurring missense mutations in the U2AF2 gene. We determine ultra-high-resolution structures of the U2AF2 RNA recognition motifs (RRM1 and RRM2) at 1.1 Å resolution and map the structural locations of the mutated U2AF2 residues. Comparison with prior, lower-resolution structures of the tandem U2AF2 RRMs in the RNA-bound and apo states reveals clusters of cancer-associated mutations at the U2AF2 RRM–RNA or apo-RRM1–RRM2 interfaces. Although the role of U2AF2 mutations in malignant transformation remains uncertain, our results show that cancer-associated mutations correlate with functionally important surfaces of the U2AF2 splicing factor.

中文翻译：

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U2AF2 RNA识别母题的高分辨率结构上映射的癌症相关的突变。

前mRNA剪接因子的获得性点突变在癌症，白血病和相关肿瘤中复发。几项研究已经确定，通常可识别3'剪接位点连接的U2AF1亚基的体细胞突变在骨髓增生异常综合症中复发。U2AF2剪接因子将大多数3'剪接位点之前的聚嘧啶信号识别为U2AF1的异二聚体。与经过深入研究的U2AF1亚基相反，缺乏与癌症相关的U2AF2突变及其结构关系的描述。在这里，我们调查了与癌症相关的突变的数据库，并确定了U2AF2基因中反复出现的错义突变。我们确定超高分辨率的U2AF2 RNA识别基序（RRM1​​和RRM2）在1.1Å分辨率的结构，并绘制了突变的U2AF2残基的结构位置。与先前的较低分辨率的串联U2AF2 RRM处于RNA结合状态和载脂蛋白状态的比较显示，在U2AF2 RRM–RNA或apo-RRM1–RRM2接口处出现了与癌症相关的突变簇。尽管U2AF2突变在恶性转化中的作用仍不确定，但我们的结果表明，与癌症相关的突变与U2AF2剪接因子的功能重要表面相关。