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.
Yong Zhu  1 ,  Xiuye Wang  1 ,  Elmira Forouzmand  2 ,  Joshua Jeong  1 ,  Feng Qiao  3 ,  Gregory A Sowd  4 ,  Alan N Engelman  4 ,  Xiaohui Xie  2 ,  Klemens J Hertel  1 ,  Yongsheng Shi  5
Affiliations
  • 1. Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
  • 2. Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA; Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA.
  • 3. Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
  • 4. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 5. Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: [email protected].
PMID: 29276085 DOI: 10.1016/j.molcel.2017.11.031
Abstract

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.