Alternatively spliced T-cell receptor transcripts are up-regulated in response to disruption of either splicing elements or reading frame

被引:27
作者
Chang, Yao-Fu [1 ]
Chan, Wai-Kin [1 ]
Imam, J. Saadi [1 ]
Wilkinson, Miles F. [1 ]
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA
关键词
D O I
10.1074/jbc.M704372200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 nonsensemediated decay ( NMD), an RNA surveillance pathway that degrades transcripts harboring PTCs. Asecond 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 thatNASis triggered when nonsense mutations disrupt exonic splicing enhancers ( ESEs). Using T-cell receptor-beta( TCR beta), 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 beta 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 beta 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.
引用
收藏
页码:29738 / 29747
页数:10
相关论文
共 67 条
[1]   Conventional 3′ end formation is not required for NMD substrate recognition in Saccharomyces cerevisiae [J].
Baker, Kristian E. ;
Parker, Roy .
RNA, 2006, 12 (08) :1441-1445
[2]   The exon junction core complex is locked onto RNA by inhibition of eIF4AIII ATPase activity [J].
Ballut, L ;
Marchadier, B ;
Baguet, A ;
Tomasetto, C ;
Séraphin, B ;
Le Hir, H .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2005, 12 (10) :861-869
[3]   Ribosome components are associated with sites of transcription [J].
Brogna, S ;
Sato, TA ;
Rosbash, M .
MOLECULAR CELL, 2002, 10 (01) :93-104
[4]   Alternative splicing induced by nonsense mutations in the immunoglobulin μ VDJ exon is independent of truncation of the open reading frame [J].
Bühler, M ;
Mühlemann, O .
RNA, 2005, 11 (02) :139-146
[5]   Intranuclear degradation of nonsense codon-containing mRNA [J].
Bühler, M ;
Wilkinson, MF ;
Mühlemann, O .
EMBO REPORTS, 2002, 3 (07) :646-651
[6]   EJC-independent degradation of nonsense immunoglobulin-μ mRNA depends on 3′ UTR length [J].
Bühler, M ;
Steiner, S ;
Mohn, F ;
Paillusson, A ;
Mühlemann, O .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2006, 13 (05) :462-464
[7]   A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer [J].
Caputi, M ;
Kendzior, RJ ;
Beemon, KL .
GENES & DEVELOPMENT, 2002, 16 (14) :1754-1759
[8]   Listening to silence and understanding nonsense: Exonic mutations that affect splicing [J].
Cartegni, L ;
Chew, SL ;
Krainer, AR .
NATURE REVIEWS GENETICS, 2002, 3 (04) :285-298
[9]   ESEfinder: a web resource to identify exonic splicing enhancers [J].
Cartegni, L ;
Wang, JH ;
Zhu, ZW ;
Zhang, MQ ;
Krainer, AR .
NUCLEIC ACIDS RESEARCH, 2003, 31 (13) :3568-3571
[10]   A splicing-dependent regulatory mechanism that detects translation signals [J].
Carter, MS ;
Li, SL ;
Wilkinson, MF .
EMBO JOURNAL, 1996, 15 (21) :5965-5975