Non-ATG-initiated translation directed by microsatellite expansions
| Autor: | Colleen L. Forster, Melissa Ingram, Benedikt Schoser, Tao Zu, Brian Gibbens, Nikunj V. Somia, Aline Huguet, Noelle S. Doty, Laura P.W. Ranum, Mark Peterson, Mário Gomes-Pereira, Stephen C. Schmechel, Walter C. Low, Matthew D. Stone, Jamie M. Margolis, Maurice S. Swanson, Todd W. Markowski, Peter B. Bitterman, Zhenhong Nan, Melinda L. Moseley, Geneviève Gourdon, H. Brent Clark |
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| Rok vydání: | 2010 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Genetic Vectors Immunoblotting Molecular Sequence Data Codon Initiator Fluorescent Antibody Technique Biology Mass Spectrometry Cell Line Eukaryotic translation Start codon medicine Humans Immunoprecipitation Myotonic Dystrophy Spinocerebellar Ataxias Amino Acid Sequence Cloning Molecular DNA Primers Genetics Multidisciplinary Reverse Transcriptase Polymerase Chain Reaction Lentivirus Translation (biology) DNA Repeat Expansion Biological Sciences medicine.disease Blotting Northern Immunohistochemistry C9orf72 Protein Mutagenesis Protein Biosynthesis Ran Spinocerebellar ataxia Trinucleotide repeat expansion Peptides Trinucleotide Repeat Expansion |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 108(1) |
| ISSN: | 1091-6490 |
| Popis: | Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders. |
| Databáze: | OpenAIRE |
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