Nucleic Acids Research Advance Access published online on November 12, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn829
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Gene regulation, Chromatin and Epigenetics |
Functional characterization of alternatively spliced human SECISBP2 transcript variants
1Signal Transduction Laboratory, Queensland Institute of Medical Research, 300 Herston Rd, 4029 Herston, Queensland, Australia, 2Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA, 3School of Biomolecular and Biomedical Science, Eskitis Institute for Cell and Molecular Therapies, Griffith University, 4111 Nathan, Queensland, Australia and 4Department of Biochemistry and Redox Biology Center, University of Nebraska, Lincoln NE 68588, USA
*To whom correspondence should be addressed. Tel: +61 7 3362 0338; Email: kumkumK{at}qimr.edu.au
Correspondence may also be addressed to Laura V. Papp. Tel: +61 7 3845 3738; Email: Laurap{at}qimr.edu.au
Received July 10, 2008. Revised October 10, 2008. Accepted October 14, 2008.
Synthesis of selenoproteins depends on decoding of the UGA stop codon as the amino acid selenocysteine (Sec). This process requires the presence of a Sec insertion sequence element (SECIS) in the 3'-untranslated region of selenoprotein mRNAs and its interaction with the SECIS binding protein 2 (SBP2). In humans, mutations in the SBP2-encoding gene Sec insertion sequence binding protein 2 (SECISBP2) that alter the amino acid sequence or cause splicing defects lead to abnormal thyroid hormone metabolism. Herein, we present the first in silico and in vivo functional characterization of alternative splicing of SECISBP2. We report a complex splicing pattern in the 5'-region of human SECISBP2, wherein at least eight splice variants encode five isoforms with varying N-terminal sequence. One of the isoforms, mtSBP2, contains a mitochondrial targeting sequence and localizes to mitochondria. Using a minigene-based in vivo splicing assay we characterized the splicing efficiency of several alternative transcripts, and show that the splicing event that creates mtSBP2 can be modulated by antisense oligonucleotides. Moreover, we show that full-length SBP2 and some alternatively spliced variants are subject to a coordinated transcriptional and translational regulation in response to ultraviolet type A irradiation-induced stress. Overall, our data broadens the functional scope of a housekeeping protein essential to selenium metabolism.
Present addresses: Junning Wang, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics (HPCGG), New Research Building, Room 164, 77 Avenue Louis Pasteur, Boston MA 02115. Ravindra N. Singh, Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
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