1. Academic Validation
  2. Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation

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

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: yongshes@uci.edu.
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.

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