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ATM-Dependent Phosphorylation of MEF2D Promotes Neuronal Survival after DNA Damage
- Source :
- The Journal of Neuroscience. 34:4640-4653
- Publication Year :
- 2014
- Publisher :
- Society for Neuroscience, 2014.
-
Abstract
- Mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a kinase critical for the normal DNA damage response, cause the neurodegenerative disorder ataxia-telangiectasia (AT). The substrates of ATM in the brain are poorly understood. Here we demonstrate that ATM phosphorylates and activates the transcription factor myocyte enhancer factor 2D (MEF2D), which plays a critical role in promoting survival of cerebellar granule cells. ATM associates with MEF2D after DNA damage and phosphorylates the transcription factor at four ATM consensus sites. Knockdown of endogenous MEF2D with a short-hairpin RNA (shRNA) increases sensitivity to etoposide-induced DNA damage and neuronal cell death. Interestingly, substitution of endogenous MEF2D with an shRNA-resistant phosphomimetic MEF2D mutant protects cerebellar granule cells from cell death after DNA damage, whereas an shRNA-resistant nonphosphorylatable MEF2D mutant does not.In vivo, cerebella inMef2dknock-out mice manifest increased susceptibility to DNA damage. Together, our results show that MEF2D is a substrate for phosphorylation by ATM, thus promoting survival in response to DNA damage. Moreover, dysregulation of the ATM–MEF2D pathway may contribute to neurodegeneration in AT.
- Subjects :
- Male
Programmed cell death
Cell Survival
DNA damage
DNA repair
Mutant
Ataxia Telangiectasia Mutated Proteins
In Vitro Techniques
Biology
Mice
Superoxides
Cerebellum
medicine
Animals
Humans
Enzyme Inhibitors
Phosphorylation
Promoter Regions, Genetic
Transcription factor
Cells, Cultured
Mice, Knockout
Neurons
Gene knockdown
MEF2 Transcription Factors
General Neuroscience
Articles
medicine.disease
Molecular biology
HEK293 Cells
Ataxia-telangiectasia
Female
RNA Interference
DNA Damage
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....9e9f8c58b5bedfe12bcb720261af0724