Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation

Mol Cell. 2018 Jan 4;69(1):62-74.e4. doi: 10.1016/j.molcel.2017.11.031. Epub 2017 Dec 21.


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.

Keywords: RNA-binding proteins; SR proteins; alternative polyadenylation; cleavage; mRNA 3′ processing; polyadenylation; splicing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Cell Line
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation / genetics*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Phosphorylation
  • Poly A / metabolism
  • Polyadenylation*
  • Protein Domains / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism
  • Sf9 Cells
  • Spodoptera
  • mRNA Cleavage and Polyadenylation Factors / metabolism*


  • FIP1L1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • cleavage factor Im, human
  • mRNA Cleavage and Polyadenylation Factors
  • Poly A