Wu, S;Mariotti, M;Santesmasses, D;Hill, KE;Baclaocos, J;Aparicio-Prat, E;Li, SP;Mackrill, J;Wu, YY;Howard, MT;Capecchi, M;Guigo, R;Burk, RF;Atkins, JF

2016

November

Open Biology

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

Validated

WOS: 10 ()

OPEN READING FRAME NONSENSE-MEDIATED DECAY TRANSLATION INITIATION-FACTORS SELENIUM-TRANSPORT PROTEIN 3 UNTRANSLATED REGION SELENOCYSTEINE INCORPORATION UGA CODONS RAT PLASMA SEQUENCE ALIGNMENT BINDING PROTEIN

6

Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 30 UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 30 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 50 sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity.

LONDON

2046-2441

10.1098/rsob.160241