| Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia. | |
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MedLine Citation:
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PMID: 18408079 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in ATM (Ataxia telangiectasia mutated) result in Ataxia telangiectasia (A-T), a disorder characterized by progressive neurodegeneration. Despite advances in understanding how ATM signals cell cycle arrest, DNA repair, and apoptosis in response to DNA damage, it remains unclear why loss of ATM causes degeneration of post-mitotic neurons and why the neurological phenotype of ATM-null individuals varies in severity. To address these issues, we generated a Drosophila model of A-T. RNAi knockdown of ATM in the eye caused progressive degeneration of adult neurons in the absence of exogenously induced DNA damage. Heterozygous mutations in select genes modified the neurodegeneration phenotype, suggesting that genetic background underlies variable neurodegeneration in A-T. The neuroprotective activity of ATM may be negatively regulated by deacetylation since mutations in a protein deacetylase gene, RPD3, suppressed neurodegeneration, and a human homolog of RPD3, histone deacetylase 2, bound ATM and abrogated ATM activation in cell culture. Moreover, knockdown of ATM in post-mitotic neurons caused cell cycle re-entry, and heterozygous mutations in the cell cycle activator gene String/CDC25 inhibited cell cycle re-entry and neurodegeneration. Thus, we hypothesize that ATM performs a cell cycle checkpoint function to protect post-mitotic neurons from degeneration and that cell cycle re-entry causes neurodegeneration in A-T. |
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Authors:
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Stacey A Rimkus; Rebeccah J Katzenberger; Anthony T Trinh; Gerald E Dodson; Randal S Tibbetts; David A Wassarman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2008-04-11 |
Journal Detail:
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Title: Genes & development Volume: 22 ISSN: 0890-9369 ISO Abbreviation: Genes Dev. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-05-02 Completed Date: 2008-06-30 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 8711660 Medline TA: Genes Dev Country: United States |
Other Details:
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Languages: eng Pagination: 1205-20 Citation Subset: IM |
Affiliation:
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Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Genetically Modified Apoptosis / genetics, physiology Ataxia Telangiectasia / genetics*, physiopathology Cell Cycle / genetics*, physiology Cell Cycle Proteins / genetics, metabolism Cell Line DNA Replication DNA-Binding Proteins / genetics, metabolism Disease Models, Animal Drosophila / genetics, physiology, ultrastructure Drosophila Proteins / genetics*, metabolism Eye / metabolism, ultrastructure Female Flow Cytometry Fluorescent Antibody Technique Green Fluorescent Proteins / genetics, metabolism Hu Paraneoplastic Encephalomyelitis Antigens / genetics, metabolism Humans Male Microscopy, Electron, Scanning Microscopy, Electron, Transmission Mutation* Nerve Degeneration / genetics*, physiopathology Neurons / cytology, metabolism, ultrastructure Protein Tyrosine Phosphatases / genetics*, metabolism Protein-Serine-Threonine Kinases / genetics, metabolism RNA Interference Tumor Suppressor Proteins / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM 067868/GM/NIGMS NIH HHS; R01 NS059001/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Drosophila Proteins; 0/ELAV protein, Drosophila; 0/Hu Paraneoplastic Encephalomyelitis Antigens; 0/Tumor Suppressor Proteins; 147336-22-9/Green Fluorescent Proteins; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein; EC 3.1.3.48/Protein Tyrosine Phosphatases; EC 3.1.3.48/stg protein, Drosophila |
| Comments/Corrections | |
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