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J. Biol. Chem., Vol. 282, Issue 41, 29738-29747, October 12, 2007

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Alternatively Spliced T-cell Receptor Transcripts Are Up-regulated in Response to Disruption of Either Splicing Elements or Reading Frame^*

From the Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Nonsense mutations create premature termination codons (PTCs), leading to the generation of truncated proteins, some of which have deleterious gain-of-function or dominant-negative activity. Protecting cells from such aberrant proteins is non-sense-mediated decay (NMD), an RNA surveillance pathway that degrades transcripts harboring PTCs. A second response to nonsense mutations is the up-regulation of alternatively spliced transcripts that skip the PTC. This nonsense-associated altered splicing (NAS) response has the potential to rescue protein function, but the mechanism by which it is triggered has been controversial. Some studies suggest that, like NMD, NAS is triggered as a result of nonsense mutations disrupting reading frame, whereas other studies suggest that NAS is triggered when nonsense mutations disrupt exonic splicing enhancers (ESEs). Using T-cell receptor- (TCR), which naturally acquires PTCs at high frequency, we provide evidence that both mechanisms act on a single type of mRNA. Mutations that disrupt consensus ESE sites up-regulated an alternatively spliced TCR transcript that skipped the mutations independently of reading frame disruption and the NMD factor UPF1. In contrast, reading frame-disrupting mutations that did not disrupt consensus ESE sites elicited UPF1-dependent up-regulation of the alternatively spliced TCR transcript. Restoration of reading frame prevented this up-regulation. Our results suggest that the response of an mRNA to a nonsense mutation depends on its context.

Received for publication, May 29, 2007 , and in revised form, August 7, 2007.

^* This study was supported by National Institutes of Health Grant GM-058595 and National Science Foundation Grant MCB-01316793. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1000, Houston, TX 77030. Tel.: 713-563-3215; Fax: 713-834-6397; E-mail: mwilkins{at}mdanderson.org.

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