title: Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements.
abstract: Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 3' UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 3' of SECIS 2, two further sites were identified with one resulting in 10-25% of the mRNA lacking SECIS 2. To address function, mutant mice were generated with either SECIS 1 or SECIS 2 deleted or with the first UGA substituted with a serine codon. They were fed on either high or selenium-deficient diets. The mutants had very different effects on the proportions of shorter and longer product Sepp1 protein isoforms isolated from plasma, and on viability. Spatially and functionally distinctive effects of the two SECIS elements on UGA decoding were inferred. We also bioinformatically identify two selenoprotein S mRNAs with different 5' sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity.
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, People's Republic of China.
authors.forename: Sen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Center for Genomic Regulation, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: Mariotti
authors.affiliation: Center for Genomic Regulation, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Didac
authors.initials: D
authors.lastname: Santesmasses
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Hill
authors.affiliation: Department of Biochemistry, University College Cork, Cork, Republic of Ireland.
authors.forename: Janinah
authors.initials: J
authors.lastname: Baclaocos
authors.affiliation: Center for Genomic Regulation, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Estel
authors.initials: E
authors.lastname: Aparicio-Prat
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, People's Republic of China.
authors.forename: Shuping
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Physiology, University College Cork, Cork, Republic of Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Mackrill
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 8412-5330, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 8412-5330, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Howard
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 8412-5330, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Capecchi
authors.affiliation: Center for Genomic Regulation, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigó
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Burk
authors.affiliation: Department of Biochemistry, University College Cork, Cork, Republic of Ireland j.atkins@ucc.ie.|Department of Human Genetics, University of Utah, Salt Lake City, UT 8412-5330, USA.
authors.forename: John F
authors.identifier: 0000-0001-7933-0165
authors.initials: JF
authors.lastname: Atkins
mesh_terms: D020413:3' Untranslated Regions; D017398:Alternative Splicing; D000818:Animals; D018388:Codon, Terminator; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D012643:Selenium / Q000378:metabolism; D017279:Selenocysteine / Q000235:genetics*; D051149:Selenoprotein P / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D018388:Codon, Terminator; D020033:Protein Isoforms; D012333:RNA, Messenger; C000621459:SELENOP protein, human; D051149:Selenoprotein P; D017279:Selenocysteine; D012643:Selenium
keywords: codon redefinition; ribosome specialization; selenocysteine; selenoprotein P; selenoprotein S