An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.
An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.
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DOI：
10.1093/nar/gkx225
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发表时间：
2017-06-20
影响因子：
14.9
通讯作者：
Ramos A
中科院分区：
文献类型：
--
作者：
Collins KM;Kainov YA;Christodolou E;Ray D;Morris Q;Hughes T;Taylor IA;Makeyev EV;Ramos A
RBM 10是一种RNA结合蛋白，在发育中起重要作用，在人类疾病中经常发生突变。RBM 10识别内含子和外显子中的多种RNA基序，并调节选择性剪接。然而，这种看似放松的序列特异性的分子机制还不清楚，功能研究仅集中在3个内含子位点。在这里，我们剖析了由RBM 10识别的RNA代码，并将其与该蛋白质的剪接调节功能联系起来。我们发现，一个两域RRM 1-ZnF单元识别GGA为中心的基序丰富的RBM 10外显子位点具有高亲和力和特异性，并测试，这些外显子序列的相互作用，促进外显子跳跃。重要的是，RBM 10的第二个RRM结构域（RRM 2）识别富含C的序列，这解释了其与NUMB外显子9的内含子3位点的已知相互作用有助于调节癌症中的Notch途径。总之，这些发现解释了RBM 10广泛的RNA特异性，并表明RBM 10作为剪接调节剂使用两个具有不同特异性的RNA结合单元来促进外显子跳跃。
RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1–ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interaction with the intronic 3΄ site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping.