Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay

Arneet L. Saltzman, Yoon Ki Kim, Qun Pan, Matthew M. Fagnani, Lynne E. Maquat, Benjamin J. Blencowe

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4320-4330
Number of pages11
JournalMolecular and Cellular Biology
Volume28
Issue number13
DOIs
Publication statusPublished - 2008 Jul 1

Fingerprint

Nonsense Mediated mRNA Decay
Protein Splicing
Alternative Splicing
Nonsense Codon
Spliceosomes
Genes
Introns
Exons
Proteins
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. / Saltzman, Arneet L.; Kim, Yoon Ki; Pan, Qun; Fagnani, Matthew M.; Maquat, Lynne E.; Blencowe, Benjamin J.

In: Molecular and Cellular Biology, Vol. 28, No. 13, 01.07.2008, p. 4320-4330.

Research output: Contribution to journalArticle

Saltzman, Arneet L. ; Kim, Yoon Ki ; Pan, Qun ; Fagnani, Matthew M. ; Maquat, Lynne E. ; Blencowe, Benjamin J. / Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 13. pp. 4320-4330.
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