Multiple RNA structures affect translation initiation and UGA redefinition efficiency during synthesis of selenoprotein P

Nucleic Acids Res. 2017 Dec 15;45(22):13004-13015. doi: 10.1093/nar/gkx982.


Gene-specific expansion of the genetic code allows for UGA codons to specify the amino acid selenocysteine (Sec). A striking example of UGA redefinition occurs during translation of the mRNA coding for the selenium transport protein, selenoprotein P (SELENOP), which in vertebrates may contain up to 22 in-frame UGA codons. Sec incorporation at the first and downstream UGA codons occurs with variable efficiencies to control synthesis of full-length and truncated SELENOP isoforms. To address how the Selenop mRNA can direct dynamic codon redefinition in different regions of the same mRNA, we undertook a comprehensive search for phylogenetically conserved RNA structures and examined the function of these structures using cell-based assays, in vitro translation systems, and in vivo ribosome profiling of liver tissue from mice carrying genomic deletions of 3' UTR selenocysteine-insertion-sequences (SECIS1 and SECIS2). The data support a novel RNA structure near the start codon that impacts translation initiation, structures located adjacent to UGA codons, additional coding sequence regions necessary for efficient production of full-length SELENOP, and distinct roles for SECIS1 and SECIS2 at UGA codons. Our results uncover a remarkable diversity of RNA elements conducting multiple occurrences of UGA redefinition to control the synthesis of full-length and truncated SELENOP isoforms.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Codon, Initiator / genetics*
  • Codon, Terminator / genetics*
  • Humans
  • Mice, Inbred C57BL
  • Nucleic Acid Conformation
  • Peptide Chain Initiation, Translational*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Ribosomes / genetics
  • Ribosomes / metabolism
  • Selenocysteine / genetics
  • Selenocysteine / metabolism
  • Selenoprotein P / genetics*
  • Selenoprotein P / metabolism
  • Sequence Homology, Nucleic Acid


  • 3' Untranslated Regions
  • Codon, Initiator
  • Codon, Terminator
  • Protein Isoforms
  • RNA, Messenger
  • Selenoprotein P
  • Selenocysteine