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PMID:18408079

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Citation

Rimkus, SA, Katzenberger, RJ, Trinh, AT, Dodson, GE, Tibbetts, RS and Wassarman, DA (2008) Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia. Genes Dev. 22:1205-20

Abstract

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.

Links

PubMed PMC2335316 Online version:10.1101/gad.1639608

Keywords

Animals; Animals, Genetically Modified; Apoptosis/genetics; Apoptosis/physiology; Ataxia Telangiectasia/genetics; Ataxia Telangiectasia/physiopathology; Cell Cycle/genetics; Cell Cycle/physiology; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Line; DNA Replication; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Disease Models, Animal; Drosophila/genetics; Drosophila/physiology; Drosophila/ultrastructure; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Eye/metabolism; Eye/ultrastructure; Female; Flow Cytometry; Fluorescent Antibody Technique; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; Hu Paraneoplastic Encephalomyelitis Antigens/genetics; Hu Paraneoplastic Encephalomyelitis Antigens/metabolism; Humans; Male; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Mutation; Nerve Degeneration/genetics; Nerve Degeneration/physiopathology; Neurons/cytology; Neurons/metabolism; Neurons/ultrastructure; Protein Tyrosine Phosphatases/genetics; Protein Tyrosine Phosphatases/metabolism; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:ATM

involved_in

GO:2000134: negative regulation of G1/S transition of mitotic cell cycle

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0003525

P

Seeded From UniProt

complete

DROME:ATM

involved_in

GO:0045494: photoreceptor cell maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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