title: Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia.
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.
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Rimkus
authors.forename: Rebeccah J
authors.initials: RJ
authors.lastname: Katzenberger
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Trinh
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Dodson
authors.forename: Randal S
authors.initials: RS
authors.lastname: Tibbetts
authors.forename: David A
authors.initials: DA
authors.lastname: Wassarman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000503:physiopathology; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051959:ELAV Proteins; C498009:ELAV protein, Drosophila; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; C059217:stg protein, Drosophila