Alternative mRNA processing is a critical mechanism for proteome expansion and gene regulation in higher eukaryotes. The SR family proteins play important roles in splicing regulation. Intriguingly, mammalian genomes encode many poorly characterized SR-like proteins, including subunits of the mRNA 3′-processing factor CFIm, CFIm68 and CFIm59. Here we demonstrate that CFIm functions as an enhancer-dependent activator of mRNA 3′ processing. CFIm regulates global alternative polyadenylation (APA) by specifically binding and activating enhancer-containing poly(A) sites (PASs). Importantly, the CFIm activator functions are mediated by the arginine-serine repeat (RS) domains of CFIm68/59, which bind specifically to an RS-like region in the CPSF subunit Fip1, and this interaction is inhibited by CFIm68/59 hyper-phosphorylation. The remarkable functional similarities between CFIm and SR proteins suggest that interactions between RS-like domains in regulatory and core factors may provide a common activation mechanism for mRNA 3′ processing, splicing, and potentially other steps in RNA metabolism.

替代性的mRNA加工是高级真核生物中蛋白质组扩展和基因调控的关键机制。SR家族蛋白在剪接调控中起重要作用。有趣的是，哺乳动物基因组编码许多特征不佳的SR样蛋白，包括mRNA 3'加工因子CFIm，CFIm68和CFIm59的亚基。在这里，我们证明CFIm充当mRNA 3'加工的增强子依赖性激活剂。CFIm通过特异性结合和激活包含增强子的聚腺苷酸位点（PAS）来调节整体性聚腺苷酸化（APA）。重要的是，CFIm激活剂功能由CFIm68 / 59的精氨酸-丝氨酸重复（RS）域介导，该域与CPSF亚基Fip1中的RS样区域特异性结合，并且这种相互作用被CFIm68 / 59的过度磷酸化抑制。