Mariotti, MarcoShetty, SumangalaBaird, LisaWu, SenLoughran, GaryCopeland, Paul R.Atkins, John F.Howard, Michael T.2018-01-182017Mariotti, Marco, Sumangala Shetty, Lisa Baird, Sen Wu, Gary Loughran, Paul R. Copeland, John F. Atkins, and Michael T. Howard. 2017. “Multiple RNA structures affect translation initiation and UGA redefinition efficiency during synthesis of selenoprotein P.” Nucleic Acids Research 45 (22): 13004-13015. doi:10.1093/nar/gkx982. http://dx.doi.org/10.1093/nar/gkx982.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34651781Abstract 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.en-USJournal Article2018-01-1810.1093/nar/gkx982