Impaired Control of IRES-Mediated Translation in X-Linked Dyskeratosis Congenita
| Autor: | Andrew, Yoon, Guang, Peng, Yves, Brandenburger, Yves, Brandenburg, Ornella, Zollo, Wei, Xu, Eduardo, Rego, Davide, Ruggero |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Proteomics bcl-X Protein Cell Cycle Proteins Insect Viruses X-Linked Inhibitor of Apoptosis Protein Biology Transfection Ribosome Dyskeratosis Congenita Dyskerin Cell Line Mice medicine Protein biosynthesis Animals Humans Point Mutation RNA Viruses Lymphocytes RNA Messenger Cells Cultured Oligonucleotide Array Sequence Analysis Genetics Multidisciplinary Nuclear Proteins RNA Translation (biology) medicine.disease Genetic translation Cell biology Internal ribosome entry site RNA Ribosomal Polyribosomes Protein Biosynthesis 5' Untranslated Regions Cyclin-Dependent Kinase Inhibitor p27 Pseudouridine Dyskeratosis congenita |
| Zdroj: | Science. 312:902-906 |
| ISSN: | 1095-9203 0036-8075 |
| Popis: | The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)–dependent translation in Dkc1 m mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1 m ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer. |
| Databáze: | OpenAIRE |
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