Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online September 12, 2002
Science DOI: 10.1126/science.1074428

Reports

Submitted on May 28, 2002
Accepted on July 12, 2002

Separable Roles for rent1/hUpf1 in Altered Splicing and Decay of Nonsense Transcripts

Joshua T. Mendell 1, Colette M. J. ap Rhys 2, Harry C. Dietz 3*

1 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 858 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.
2 Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 858 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.
3 Institute of Genetic Medicine and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 858 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.

* To whom correspondence should be addressed. E-mail: hdietz{at}jhmi.edu.

The mechanism by which disruption of reading frame can influence pre-mRNA processing is poorly understood. We assessed the role of factors essential for nonsense-mediated mRNA decay (NMD) in nonsense-mediated altered splicing (NAS) using RNA interference (RNAi) in mammalian cells. Inhibition of rent1/hUpf1 expression abrogated both NMD and NAS of nonsense T-cell receptor-ß (TCR-ß) transcripts. In contrast, inhibition of rent2/hUpf2 expression did not disrupt NAS despite achieving comparable stabilization of nonsense transcripts. We also demonstrate that NAS and NMD are genetically separable functions of rent1/hUpf1. Additionally, rent1/hUpf1 enters the nucleus where it may directly influence early events in mRNA biogenesis. This provides compelling evidence that NAS relies upon a component of the nonsense surveillance machinery but is not an indirect consequence of NMD.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption.
J. S. Imam, J. P. Gudikote, W.-k. Chan, and M. F. Wilkinson (2009)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
A new MIF4G domain-containing protein, CTIF, directs nuclear cap-binding protein CBP80/20-dependent translation.
K. M. Kim, H. Cho, K. Choi, J. Kim, B.-W. Kim, Y.-G. Ko, S. K. Jang, and Y. K. Kim (2009)
Genes & Dev. 23, 2033-2045
   Abstract »    Full Text »    PDF »
Inhibition of Nonsense-mediated mRNA Decay by the Natural Product Pateamine A through Eukaryotic Initiation Factor 4AIII.
Y. Dang, W.-K. Low, J. Xu, N. H. Gehring, H. C. Dietz, D. Romo, and J. O. Liu (2009)
J. Biol. Chem. 284, 23613-23621
   Abstract »    Full Text »    PDF »
Two Molecular Pathways (NMD and ERAD) Contribute to a Genetic Epilepsy Associated with the GABAA Receptor GABRA1 PTC Mutation, 975delC, S326fs328X.
J.-Q. Kang, W. Shen, and R. L. Macdonald (2009)
J. Neurosci. 29, 2833-2844
   Abstract »    Full Text »    PDF »
Nonsense Codons Trigger an RNA Partitioning Shift.
A. D. Bhalla, J. P. Gudikote, J. Wang, W.-K. Chan, Y.-F. Chang, O. R. Olivas, and M. F. Wilkinson (2009)
J. Biol. Chem. 284, 4062-4072
   Abstract »    Full Text »    PDF »
A nonsense exon in the Tpm1 gene is silenced by hnRNP H and F.
J. L. Coles, M. Hallegger, and C. W.J. Smith (2009)
RNA 15, 33-43
   Abstract »    Full Text »    PDF »
SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs.
C. Gong, Y. K. Kim, C. F. Woeller, Y. Tang, and L. E. Maquat (2009)
Genes & Dev. 23, 54-66
   Abstract »    Full Text »    PDF »
Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation.
L. Ajamian, L. Abrahamyan, M. Milev, P. V. Ivanov, A. E. Kulozik, N. H. Gehring, and A. J. Mouland (2008)
RNA 14, 914-927
   Abstract »    Full Text »    PDF »
The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus.
L. Agranat, O. Raitskin, J. Sperling, and R. Sperling (2008)
PNAS 105, 5028-5033
   Abstract »    Full Text »    PDF »
A Premature Termination Codon Mutation at the C Terminus of Foamy Virus Gag Downregulates the Levels of Spliced pol mRNA.
E.-G. Lee, D. Kuppers, M. Horn, J. Roy, C. May, and M. L. Linial (2008)
J. Virol. 82, 1656-1664
   Abstract »    Full Text »    PDF »
Alternatively Spliced T-cell Receptor Transcripts Are Up-regulated in Response to Disruption of Either Splicing Elements or Reading Frame.
Y.-F. Chang, W.-K. Chan, J. S. Imam, and M. F. Wilkinson (2007)
J. Biol. Chem. 282, 29738-29747
   Abstract »    Full Text »    PDF »
Alternative splicing of the ADAR1 transcript in a region that functions either as a 5'-UTR or an ORF.
S. Lykke-Andersen, S. Pinol-Roma, and J. Kjems (2007)
RNA 13, 1732-1744
   Abstract »    Full Text »    PDF »
Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies.
S. Durand, N. Cougot, F. Mahuteau-Betzer, C.-H. Nguyen, D. S. Grierson, E. Bertrand, J. Tazi, and F. Lejeune (2007)
J. Cell Biol. 178, 1145-1160
   Abstract »    Full Text »    PDF »
Caenorhabditis elegans SMG-2 Selectively Marks mRNAs Containing Premature Translation Termination Codons.
L. Johns, A. Grimson, S. L. Kuchma, C. L. Newman, and P. Anderson (2007)
Mol. Cell. Biol. 27, 5630-5638
   Abstract »    Full Text »    PDF »
Introns play an essential role in splicing-dependent formation of the exon junction complex.
T. Ideue, Y. T.F. Sasaki, M. Hagiwara, and T. Hirose (2007)
Genes & Dev. 21, 1993-1998
   Abstract »    Full Text »    PDF »
Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function.
O. Isken and L. E. Maquat (2007)
Genes & Dev. 21, 1833-3856
   Abstract »    Full Text »    PDF »
The abundance of RNPS1, a protein component of the exon junction complex, can determine the variability in efficiency of the Nonsense Mediated Decay pathway.
M. H. Viegas, N. H. Gehring, S. Breit, M. W. Hentze, and A. E. Kulozik (2007)
Nucleic Acids Res. 35, 4542-4551
   Abstract »    Full Text »    PDF »
Nonsense Mutations in hERG Cause a Decrease in Mutant mRNA Transcripts by Nonsense-Mediated mRNA Decay in Human Long-QT Syndrome.
Q. Gong, L. Zhang, G. M. Vincent, B. D. Horne, and Z. Zhou (2007)
Circulation 116, 17-24
   Abstract »    Full Text »    PDF »
A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.
P. L. Boutz, P. Stoilov, Q. Li, C.-H. Lin, G. Chawla, K. Ostrow, L. Shiue, M. Ares Jr., and D. L. Black (2007)
Genes & Dev. 21, 1636-1652
   Abstract »    Full Text »    PDF »
Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay.
J. Z. Ni, L. Grate, J. P. Donohue, C. Preston, N. Nobida, G. O'Brien, L. Shiue, T. A. Clark, J. E. Blume, and M. Ares Jr. (2007)
Genes & Dev. 21, 708-718
   Abstract »    Full Text »    PDF »
Upf1/Upf2 Regulation of 3' Untranslated Region Splice Variants of AUF1 Links Nonsense-Mediated and A+U-Rich Element-Mediated mRNA Decay.
L. Banihashemi, G. M. Wilson, N. Das, and G. Brewer (2006)
Mol. Cell. Biol. 26, 8743-8754
   Abstract »    Full Text »    PDF »
The canonical UPF1-dependent nonsense-mediated mRNA decay is inhibited in transcripts carrying a short open reading frame independent of sequence context.
A. L. Silva, F. J.C. Pereira, A. Morgado, J. Kong, R. Martins, P. Faustino, S. A. Liebhaber, and L. Romao (2006)
RNA 12, 2160-2170
   Abstract »    Full Text »    PDF »
Crystal structure of the UPF2-interacting domain of nonsense-mediated mRNA decay factor UPF1.
J. Kadlec, D. Guilligay, R. B. Ravelli, and S. Cusack (2006)
RNA 12, 1817-1824
   Abstract »    Full Text »    PDF »
AUG sequences are required to sustain nonsense-codon-mediated suppression of splicing.
E. Kamhi, G. Yahalom, G. Kass, Y. Hacham, R. Sperling, and J. Sperling (2006)
Nucleic Acids Res. 34, 3421-3433
   Abstract »    Full Text »    PDF »
Role for Upf2p Phosphorylation in Saccharomyces cerevisiae Nonsense-Mediated mRNA Decay..
W. Wang, I. J. Cajigas, S. W. Peltz, M. F. Wilkinson, and C. I. Gonzalez (2006)
Mol. Cell. Biol. 26, 3390-3400
   Abstract »    Full Text »    PDF »
Mutational analysis of human eIF4AIII identifies regions necessary for exon junction complex formation and nonsense-mediated mRNA decay..
T. SHIBUYA, T. O. TANGE, M. E. STROUPE, and M. J. MOORE (2006)
RNA 12, 360-374
   Abstract »    Full Text »    PDF »
hUPF2 Silencing Identifies Physiologic Substrates of Mammalian Nonsense-Mediated mRNA Decay.
J. Wittmann, E. M. Hol, and H.-M. Jack (2006)
Mol. Cell. Biol. 26, 1272-1287
   Abstract »    Full Text »    PDF »
Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay.
I. Kashima, A. Yamashita, N. Izumi, N. Kataoka, R. Morishita, S. Hoshino, M. Ohno, G. Dreyfuss, and S. Ohno (2006)
Genes & Dev. 20, 355-367
   Abstract »    Full Text »    PDF »
The uORF-containing thrombopoietin mRNA escapes nonsense-mediated decay (NMD)..
C. Stockklausner, S. Breit, G. Neu-Yilik, N. Echner, M. W. Hentze, A. E. Kulozik, and N. H. Gehring (2006)
Nucleic Acids Res. 34, 2355-2363
   Abstract »    Full Text »    PDF »
A 3' UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus.
J. E. WEIL and K. L. BEEMON (2006)
RNA 12, 102-110
   Abstract »    Full Text »    PDF »
CYP3A5 mRNA Degradation by Nonsense-Mediated mRNA Decay.
F. Busi and T. Cresteil (2005)
Mol. Pharmacol. 68, 808-815
   Abstract »    Full Text »    PDF »
Exon Inclusion Is Dependent on Predictable Exonic Splicing Enhancers.
X. H.-F. Zhang, T. Kangsamaksin, M. S. P. Chao, J. K. Banerjee, and L. A. Chasin (2005)
Mol. Cell. Biol. 25, 7323-7332
   Abstract »    Full Text »    PDF »
Nonsense-mediated mRNA decay in mammals.
L. E. Maquat (2005)
J. Cell Sci. 118, 1773-1776
   Full Text »    PDF »
Nonsense-associated alternative splicing of T-cell receptor {beta} genes: No evidence for frame dependence.
F. MOHN, M. BUHLER, and O. MUHLEMANN (2005)
RNA 11, 147-156
   Abstract »    Full Text »    PDF »
Alternative splicing induced by nonsense mutations in the immunoglobulin {micro} VDJ exon is independent of truncation of the open reading frame.
M. BUHLER and O. MUHLEMANN (2005)
RNA 11, 139-146
   Abstract »    Full Text »    PDF »
Stop codon-mediated suppression of splicing is a novel nuclear scanning mechanism not affected by elements of protein synthesis and NMD.
C. WACHTEL, B. LI, J. SPERLING, and R. SPERLING (2004)
RNA 10, 1740-1750
   Abstract »    Full Text »    PDF »
SMG-1 Is a Phosphatidylinositol Kinase-Related Protein Kinase Required for Nonsense-Mediated mRNA Decay in Caenorhabditis elegans.
A. Grimson, S. O'Connor, C. L. Newman, and P. Anderson (2004)
Mol. Cell. Biol. 24, 7483-7490
   Abstract »    Full Text »    PDF »
Diversity of Vertebrate Splicing Factor U2AF35: IDENTIFICATION OF ALTERNATIVELY SPLICED U2AF1 mRNAs.
T. R. Pacheco, A. Q. Gomes, N. L. Barbosa-Morais, V. Benes, W. Ansorge, M. Wollerton, C. W. Smith, J. Valcarcel, and M. Carmo-Fonseca (2004)
J. Biol. Chem. 279, 27039-27049
   Abstract »    Full Text »    PDF »
Unspliced Rous Sarcoma Virus Genomic RNAs Are Translated and Subjected to Nonsense-Mediated mRNA Decay before Packaging.
J. J. LeBlanc and K. L. Beemon (2004)
J. Virol. 78, 5139-5146
   Abstract »    Full Text »    PDF »
Translation repression by GLD-1 protects its mRNA targets from nonsense-mediated mRNA decay in C. elegans.
M.-H. Lee and T. Schedl (2004)
Genes & Dev. 18, 1047-1059
   Abstract »    Full Text »    PDF »
Premature termination codons do not affect the rate of splicing of neighboring introns.
J. R. LYTLE and J. A. STEITZ (2004)
RNA 10, 657-668
   Abstract »    Full Text »    PDF »
A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions in nonsense-mediated decay.
M. A. Ferraiuolo, C.-S. Lee, L. W. Ler, J. L. Hsu, M. Costa-Mattioli, M.-J. Luo, R. Reed, and N. Sonenberg (2004)
PNAS 101, 4118-4123
   Abstract »    Full Text »    PDF »
Molecular cross-talk between the transcription, translation, and nonsense-mediated decay machineries.
F. J. Iborra, A. E. Escargueil, K. Y. Kwek, A. Akoulitchev, and P. R. Cook (2004)
J. Cell Sci. 117, 899-906
   Abstract »    Full Text »    PDF »
Regulation of splicing: The importance of being translatable.
E. MIRIAMI, R. SPERLING, J. SPERLING, and U. MOTRO (2004)
RNA 10, 1-4
   Abstract »    Full Text »    PDF »
RNA Interference in Biology and Medicine.
O. Milhavet, D. S. Gary, and M. P. Mattson (2003)
Pharmacol. Rev. 55, 629-648
   Abstract »    Full Text »    PDF »
A frameshifting mutation in CHRNE unmasks skipping of the preceding exon.
K. Ohno, M. Milone, X.-M. Shen, and A. G. Engel (2003)
Hum. Mol. Genet. 12, 3055-3066
   Abstract »    Full Text »    PDF »
A Hox gene mutation that triggers nonsense-mediated RNA decay and affects alternative splicing during Drosophila development.
C. R. Alonso and M. Akam (2003)
Nucleic Acids Res. 31, 3873-3880
   Abstract »    Full Text »    PDF »
Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage.
J. F. Bateman, S. Freddi, G. Nattrass, and R. Savarirayan (2003)
Hum. Mol. Genet. 12, 217-225
   Abstract »    Full Text »    PDF »
Nuclear translation: What is the evidence?.
J. E. DAHLBERG, E. LUND, and E. B. GOODWIN (2003)
RNA 9, 1-8
   Abstract »    Full Text »    PDF »
Characterization of human Smg5/7a: A protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1.
S.-Y. CHIU, G. SERIN, O. OHARA, and L. E. MAQUAT (2003)
RNA 9, 77-87
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)