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Molecular and Cellular Biology, July 2008, p. 4320-4330, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.00361-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of Multiple Core Spliceosomal Proteins by Alternative Splicing-Coupled Nonsense-Mediated mRNA Decay ^,

Arneet L. Saltzman,^1,2 Yoon Ki Kim,^3, Qun Pan,² Matthew M. Fagnani,^1,2 Lynne E. Maquat,³ and Benjamin J. Blencowe^1,2*

Department of Molecular Genetics,¹ Banting and Best Department of Medical Research, Centre for Cellular and Biomolecular Research, 160 College Street, University of Toronto, Toronto, Ontario M5S 3E1, Canada,² Department of Biochemistry and Biophysics, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 712, University of Rochester, Rochester, New York 14642³

Received 3 March 2008/ Returned for modification 1 April 2008/ Accepted 17 April 2008

Alternative splicing (AS) can regulate gene expression by introducing premature termination codons (PTCs) into spliced mRNA that subsequently elicit transcript degradation by the nonsense-mediated mRNA decay (NMD) pathway. However, the range of cellular functions controlled by this process and the factors required are poorly understood. By quantitative AS microarray profiling, we find that there are significant overlaps among the sets of PTC-introducing AS events affected by individual knockdown of the three core human NMD factors, Up-Frameshift 1 (UPF1), UPF2, and UPF3X/B. However, the levels of some PTC-containing splice variants are less or not detectably affected by the knockdown of UPF2 and/or UPF3X, compared with the knockdown of UPF1. The intron sequences flanking the affected alternative exons are often highly conserved, suggesting important regulatory roles for these AS events. The corresponding genes represent diverse cellular functions, and surprisingly, many encode core spliceosomal proteins and assembly factors. We further show that conserved, PTC-introducing AS events are enriched in genes that encode core spliceosomal proteins. Where tested, altering the expression levels of these core spliceosomal components affects the regulation of PTC-containing splice variants from the corresponding genes. Together, our results show that AS-coupled NMD can have different UPF factor requirements and is likely to regulate many general components of the spliceosome. The results further implicate general spliceosomal components in AS regulation.

Published ahead of print on 28 April 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.