HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 31, 32170-32180, July 30, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/31/32170    most recent M405024200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inácio, A. Articles by Romão, L. Search for Related Content PubMed PubMed Citation Articles by Inácio, A. Articles by Romão, L. Social Bookmarking                      What's this?

Nonsense Mutations in Close Proximity to the Initiation Codon Fail to Trigger Full Nonsense-mediated mRNA Decay^*

Ângela Inácio, Ana Luísa Silva, Joana Pinto, Xinjun Ji¶, Ana Morgado, Fátima Almeida, Paula Faustino, João Lavinha, Stephen A. Liebhaber¶, and Luísa Romão||

From the Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisboa, Portugal and the ^¶Departments of Genetics and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs containing premature translation termination codons. In mammalian cells, a termination codon is ordinarily recognized as "premature" if it is located greater than 50–54 nucleotides 5' to the final exon-exon junction. We have described a set of naturally occurring human -globin gene mutations that apparently contradict this rule. The corresponding -thalassemia genes contain nonsense mutations within exon 1, and yet their encoded mRNAs accumulate to levels approaching wild-type -globin (^WT) mRNA. In the present report we demonstrate that the stabilities of these mRNAs with nonsense mutations in exon 1 are intermediate between ^WT mRNA and -globin mRNA carrying a prototype NMD-sensitive mutation in exon 2 (codon 39 nonsense; 39). Functional analyses of these mRNAs with 5'-proximal nonsense mutations demonstrate that their relative resistance to NMD does not reflect abnormal RNA splicing or translation re-initiation and is independent of promoter identity and erythroid specificity. Instead, the proximity of the nonsense codon to the translation initiation AUG constitutes a major determinant of NMD. Positioning a termination mutation at the 5' terminus of the coding region blunts mRNA destabilization, and this effect is dominant to the "50–54 nt boundary rule." These observations impact on current models of NMD.

Received for publication, May 5, 2004 , and in revised form, May 25, 2004.

^* This work was supported in part by Fundação para a Ciência e a Tecnologia (PRAXIS/P/SAU/63/96, POCTI/MGI/34105/2000 and Programa Plurianual/CIGMH), and by National Institutes of Health Grant RO1-HL 65449 (to S. A. L.). 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.

Supported by Fellowships from Fundação para a Ciência e a Tecnologia.

^|| To whom correspondence should be addressed. Tel.: 351-21-751-9234; Fax: 351-21-752-6410; E-mail: luisa.romao{at}insa.min-saude.pt.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. L. Silva, P. Ribeiro, A. Inacio, S. A. Liebhaber, and L. Romao Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay RNA, March 1, 2008; 14(3): 563 - 576. [Abstract] [Full Text] [PDF]

				M. A. Aldred, R. D. Machado, V. James, N. W. Morrell, and R. C. Trembath Characterization of the BMPR2 5'-Untranslated Region and a Novel Mutation in Pulmonary Hypertension Am. J. Respir. Crit. Care Med., October 15, 2007; 176(8): 819 - 824. [Abstract] [Full Text] [PDF]

				K. Hori and Y. Watanabe Context Analysis of Termination Codons in mRNA that are Recognized by Plant NMD Plant Cell Physiol., July 1, 2007; 48(7): 1072 - 1078. [Abstract] [Full Text] [PDF]

				A. L. Silva, F. J.C. Pereira, A. Morgado, J. Kong, R. Martins, P. Faustino, S. A. Liebhaber, and L. Romao The canonical UPF1-dependent nonsense-mediated mRNA decay is inhibited in transcripts carrying a short open reading frame independent of sequence context RNA, December 1, 2006; 12(12): 2160 - 2170. [Abstract] [Full Text] [PDF]

				K. Yamanegi, S. Tang, and Z.-M. Zheng Kaposi's Sarcoma-Associated Herpesvirus K8{beta} Is Derived from a Spliced Intermediate of K8 Pre-mRNA and Antagonizes K8{alpha} (K-bZIP) To Induce p21 and p53 and Blocks K8{alpha}-CDK2 Interaction J. Virol., November 15, 2005; 79(22): 14207 - 14221. [Abstract] [Full Text] [PDF]

				A. Magen and G. Ast The importance of being divisible by three in alternative splicing Nucleic Acids Res., September 28, 2005; 33(17): 5574 - 5582. [Abstract] [Full Text] [PDF]