title: ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage.
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 in Mef2d knock-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.
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, and Proteomics Facility, Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Shing Fai
authors.initials: SF
authors.lastname: Chan
authors.forename: Sam
authors.initials: S
authors.lastname: Sances
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Brill
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Okamoto
authors.forename: Rameez
authors.initials: R
authors.lastname: Zaidi
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Akhtar
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D013481:Superoxides; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: ATM; DNA damage; MEF2D; ataxia telangiectasia; neuronal survival; phosphorylation