SR protein kinases promote splicing of nonconsensus introns
SR protein kinases promote splicing of nonconsensus introns
复制标题
DOI：
10.1038/nsmb.3057
复制
发表时间：
2015-08-01
影响因子：
16.8
通讯作者：
Guthrie, Christine
中科院分区：
文献类型：
--
作者：
Lipp, Jesse J.;Marvin, Michael C.;Guthrie, Christine
剪接体的磷酸化对于RNA剪接是必不可少的，然而激酶信号传导如何以及在多大程度上影响剪接还没有在全基因组的基础上定义。使用化学遗传学方法，我们表明在裂殖酵母的SR蛋白激酶DSK1是必需的内含子与次优剪接位点的有效剪接。在裂殖酵母和人类细胞中的系统性底物图谱显示，SRPKs通过使用RXXSP共识基序进行底物识别，靶向进化上保守的剪接体蛋白，包括分支点结合蛋白Bpb1（人类中的SF1）。在体外，SF1的磷酸化增加了SF1与具有非共识剪接位点的内含子的结合，并且这些位点突变为共识减轻了体内对Dsk 1和磷酸化Bpb 1的需求。通过激酶信号传导途径调节剪接效率可能允许响应于环境和发育线索调节基因表达。
Phosphorylation of the spliceosome is essential for RNA splicing, yet how and to what extent kinase signaling affects splicing have not been defined on a genome-wide basis. Using a chemical genetic approach, we show in Schizosaccharomyces pombe that the SR protein kinase Dsk1 is required for efficient splicing of introns with suboptimal splice sites. Systematic substrate mapping in fission yeast and human cells revealed that SRPKs target evolutionarily conserved spliceosomal proteins, including the branchpoint-binding protein Bpb1 (SF1 in humans), by using an RXXSP consensus motif for substrate recognition. Phosphorylation of SF1 increases SF1 binding to introns with nonconsensus splice sites in vitro, and mutation of such sites to consensus relieves the requirement for Dsk1 and phosphorylated Bpb1 in vivo. Modulation of splicing efficiency through kinase signaling pathways may allow tuning of gene expression in response to environmental and developmental cues.