Nonsense-mediated mRNA decay in health and disease.

All eukaryotes possess the ability to detect and degrade transcripts harboring premature signals for the termination of translation. Despite the ubiquitous nature of nonsense-mediated mRNA decay (NMD) and its demonstrated role in the modulation of phenotypes resulting from selected nonsense alleles, very little is known regarding its basic mechanism or the selective pressure for complete evolutionary conservation of this function. This review will present the current models of NMD that have been generated during the study of model organisms and mammalian cells. The physiological burden of nonsense transcripts and the emerging view that NMD plays a broad and critical role in the regulation of gene expression will also be discussed. Such issues are relevant to the proposal that pharmacological manipulation of NMD will find therapeutic application.

[1]  J. Clegg,et al.  Molecular basis for dominantly inherited inclusion body beta-thalassemia. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[2]  C. Milstein,et al.  Nonsense Mutations Inhibit RNA Splicing in a Cell-Free System: Recognition of Mutant Codon Is Independent of Protein Synthesis , 1996, Cell.

[3]  H. Dietz,et al.  Maintenance of an open reading frame as an additional level of scrutiny during splice site selection , 1994, Nature Genetics.

[4]  H. Dietz,et al.  Expression of a mutant human fibrillin allele upon a normal human or murine genetic background recapitulates a Marfan cellular phenotype. , 1995, The Journal of clinical investigation.

[5]  D. Housman,et al.  Absence of Messenger RNA for Beta Globin Chain in β°-Thalassaemia , 1974, Nature.

[6]  Titus H. J. Huisman,et al.  The β- and δ-thalassemia repository , 1992 .

[7]  R Parker,et al.  Mechanisms of mRNA degradation in eukaryotes. , 1994, Trends in biochemical sciences.

[8]  L. R. Schenkman,et al.  A factor required for nonsense-mediated mRNA decay in yeast is exported from the nucleus to the cytoplasm by a nuclear export signal sequence. , 1998, Journal of cell science.

[9]  S. Peltz,et al.  mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor. , 1993, Genes & development.

[10]  J. McCarthy,et al.  The Relationship between Eukaryotic Translation and mRNA Stability , 1995, The Journal of Biological Chemistry.

[11]  J. Berman,et al.  Telomere Length Regulation and Telomeric Chromatin Require the Nonsense-Mediated mRNA Decay Pathway , 1998, Molecular and Cellular Biology.

[12]  S. Peltz,et al.  The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. , 1991, Genes & development.

[13]  M. Culbertson,et al.  Gene products that promote mRNA turnover in Saccharomyces cerevisiae , 1992, Molecular and cellular biology.

[14]  L. Chasin,et al.  Phosphoribosyltransferase Rna. Cytoplasmic Adenine Effects of Nonsense Mutations on Nuclear And , 1995 .

[15]  S. Peltz,et al.  Identification and characterization of mutations in the UPF1 gene that affect nonsense suppression and the formation of the Upf protein complex but not mRNA turnover , 1996, Molecular and cellular biology.

[16]  C. Milstein,et al.  Low cytoplasmic mRNA levels of immunoglobulin kappa light chain genes containing nonsense codons correlate with inefficient splicing. , 1994, The EMBO journal.

[17]  M. Hentze,et al.  Nuclear degradation of nonsense mutated beta-globin mRNA: a post-transcriptional mechanism to protect heterozygotes from severe clinical manifestations of beta-thalassemia? , 1995, Nucleic acids research.

[18]  S. Peltz,et al.  Genetic and biochemical characterization of mutations in the ATPase and helicase regions of the Upf1 protein , 1996, Molecular and cellular biology.

[19]  Stabilization and ribosome association of unspliced pre-mRNAs in a yeast upf1- mutant. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Parker,et al.  Premature translational termination triggers mRNA decapping , 1994, Nature.

[21]  E. Lund,et al.  Proofreading and aminoacylation of tRNAs before export from the nucleus. , 1998, Science.

[22]  F. He,et al.  Identification of a novel component of the nonsense-mediated mRNA decay pathway by use of an interacting protein screen. , 1995, Genes & development.

[23]  U. Francke,et al.  Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms. , 1994, The Journal of clinical investigation.

[24]  M. Hampsey,et al.  cis- and trans-acting suppressors of a translation initiation defect at the cyc1 locus of Saccharomyces cerevisiae. , 1992, Genetics.

[25]  F. He,et al.  Interaction between Nmd2p and Upf1p is required for activity but not for dominant-negative inhibition of the nonsense-mediated mRNA decay pathway in yeast. , 1996, RNA.

[26]  S. Peltz,et al.  Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon. , 1995, Genes & development.

[27]  G. Thomas,et al.  Impact of premature stop codons on mRNA levels in infantile Sandhoff disease. , 1994, Human molecular genetics.

[28]  S. Baserga,et al.  Nonsense mutations in the human beta-globin gene affect mRNA metabolism. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M B Roth,et al.  smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Culbertson,et al.  Identification of an additional gene required for eukaryotic nonsense mRNA turnover. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  H. Dietz,et al.  Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. , 1993, Genomics.

[32]  C. R. Valentine,et al.  The association of nonsense codons with exon skipping. , 1998, Mutation research.

[33]  M. Ruiz-Echevarría,et al.  The surveillance complex interacts with the translation release factors to enhance termination and degrade aberrant mRNAs. , 1998, Genes & development.

[34]  M. Culbertson,et al.  RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. , 1999, Trends in genetics : TIG.

[35]  S. Thein,et al.  Nonsense codon mutations in the terminal exon of the beta-globin gene are not associated with a reduction in beta-mRNA accumulation: a mechanism for the phenotype of dominant beta-thalassemia. , 1994, Blood.

[36]  D. Sillence,et al.  A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in schmid metaphyseal chondrodysplasia. , 1998, The Journal of clinical investigation.

[37]  L. Maquat,et al.  A mutated human homologue to yeast Upf1 protein has a dominant-negative effect on the decay of nonsense-containing mRNAs in mammalian cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  H. Jäck,et al.  Cloning and characterization of HUPF1, a human homolog of the Saccharomyces cerevisiae nonsense mRNA-reducing UPF1 protein. , 1997, Nucleic acids research.

[39]  M. Carter,et al.  A splicing‐dependent regulatory mechanism that detects translation signals. , 1996, The EMBO journal.

[40]  P. Anderson,et al.  mRNA surveillance mitigates genetic dominance in Caenorhabditis elegans , 1998, Molecular and General Genetics MGG.

[41]  M. Ruiz-Echevarría,et al.  Identifying the right stop: determining how the surveillance complex recognizes and degrades an aberrant mRNA , 1998, The EMBO journal.

[42]  R. Parker,et al.  Isolation and characterization of Dcp1p, the yeast mRNA decapping enzyme , 1998, The EMBO journal.

[43]  A. Hamosh,et al.  CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. , 1992, Human molecular genetics.

[44]  F. Spencer,et al.  Mammalian orthologues of a yeast regulator of nonsense transcript stability. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[45]  R. Pulak,et al.  mRNA surveillance by the Caenorhabditis elegans smg genes. , 1993, Genes & development.

[46]  M. Ruiz-Echevarría,et al.  Identification and Characterization of a Sequence Motif Involved in Nonsense-Mediated mRNA Decay , 2022 .

[47]  L. Maquat,et al.  Cytoplasmic mRNA for human triosephosphate isomerase is immune to nonsense-mediated decay despite forming polysomes. , 1996, Biochimie.

[48]  L. Maquat,et al.  Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. , 1993, Molecular and cellular biology.

[49]  A. Atkin,et al.  The majority of yeast UPF1 co-localizes with polyribosomes in the cytoplasm. , 1995, Molecular biology of the cell.

[50]  R. Losson,et al.  Interference of nonsense mutations with eukaryotic messenger RNA stability. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[51]  C. Springer,et al.  Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. , 1992, American journal of human genetics.

[52]  J. Clancy,et al.  Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line , 1997, Nature Medicine.

[53]  M. Welsh,et al.  The amino-terminal portion of CFTR forms a regulated CI− channel , 1994, Cell.

[54]  David Valle,et al.  The skipping of constitutive exons in vivo induced by nonsense mutations , 1993, Science.

[55]  L. Chasin,et al.  Nonsense mutations in the dihydrofolate reductase gene affect RNA processing , 1989, Molecular and cellular biology.

[56]  D. Housman,et al.  Absence of messenger RNA for beta globin chain in beta(0) thalassaemia. , 1974, Nature.

[57]  M. Hentze,et al.  Determination of mRNA fate by different RNA polymerase II promoters. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[58]  M. Carter,et al.  A Regulatory Mechanism That Detects Premature Nonsense Codons in T-cell Receptor Transcripts in Vivo Is Reversed by Protein Synthesis Inhibitors in Vitro* , 1995, The Journal of Biological Chemistry.

[59]  M. Shulman,et al.  On the linkage between RNA processing and RNA translatability. , 1994, The Journal of biological chemistry.

[60]  M. Ruiz-Echevarría,et al.  Making sense of nonsense in yeast. , 1996, Trends in biochemical sciences.

[61]  L. R. Schenkman,et al.  Relationship between Yeast Polyribosomes and Upf Proteins Required for Nonsense mRNA Decay* , 1997, The Journal of Biological Chemistry.

[62]  M. Potash,et al.  Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse. , 1985, The EMBO journal.

[63]  L. Maquat,et al.  At Least One Intron Is Required for the Nonsense-Mediated Decay of Triosephosphate Isomerase mRNA: a Possible Link between Nuclear Splicing and Cytoplasmic Translation , 1998, Molecular and Cellular Biology.

[64]  G. Caponigro,et al.  Mechanisms and control of mRNA turnover in Saccharomyces cerevisiae. , 1996, Microbiological reviews.

[65]  P. Hieter,et al.  Accumulation of mRNA coding for the ctf13p kinetochore subunit of Saccharomyces cerevisiae depends on the same factors that promote rapid decay of nonsense mRNAs. , 1998, Genetics.

[66]  L. Maquat,et al.  Introns are cis effectors of the nonsense-codon-mediated reduction in nuclear mRNA abundance , 1994, Molecular and cellular biology.

[67]  D. Bedwell,et al.  Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations , 1996, Nature Medicine.

[68]  R. Crystal,et al.  Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis. , 1992, The Journal of clinical investigation.

[69]  M. Hentze,et al.  Binary specification of nonsense codons by splicing and cytoplasmic translation , 1998, The EMBO journal.

[70]  P. Slonimski,et al.  NAM7 nuclear gene encodes a novel member of a family of helicases with a Zn-ligand motif and is involved in mitochondrial functions in Saccharomyces cerevisiae. , 1992, Journal of molecular biology.

[71]  M. Wickens,et al.  Life and death in the cytoplasm: messages from the 3' end. , 1997, Current opinion in genetics & development.

[72]  L. Maquat,et al.  Intron function in the nonsense-mediated decay of beta-globin mRNA: indications that pre-mRNA splicing in the nucleus can influence mRNA translation in the cytoplasm. , 1998, RNA.

[73]  L. Hood,et al.  The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. , 1986, Annual review of immunology.

[74]  V. Ambros,et al.  A new kind of informational suppression in the nematode Caenorhabditis elegans. , 1989, Genetics.

[75]  J. Steitz,et al.  A mammalian gene with introns instead of exons generating stable RNA products , 1996, Nature.

[76]  L. Naeger,et al.  Nonsense mutations inhibit splicing of MVM RNA in cis when they interrupt the reading frame of either exon of the final spliced product. , 1992, Genes & development.

[77]  E. Nanba,et al.  Expression of the beta-hexosaminidase alpha subunit gene with the four-base insertion of infantile Jewish Tay-Sachs disease. , 1991, The Journal of biological chemistry.

[78]  L. Maquat.  When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. , 1995, RNA.

[79]  A. Stopeck,et al.  Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene. , 1992, Blood.

[80]  Shulin Li,et al.  Nonsense surveillance in lymphocytes? , 1998, Immunity.

[81]  M. Wabl,et al.  Translation affects immunoglobulin mRNA stability , 1989, European journal of immunology.

[82]  G. Caponigro,et al.  An essential component of the decapping enzyme required for normal rates of mRNA turnover , 1996, Nature.

[83]  P. Anderson,et al.  smg-7 is required for mRNA surveillance in Caenorhabditis elegans. , 1999, Genetics.