title: Posttranscriptional derepression of GADD45alpha by genotoxic stress.
abstract: The growth arrest- and DNA damage-inducible gene GADD45alpha is potently upregulated in response to stress stimuli. Here, two RNA binding proteins, the mRNA decay-promoting AUF1 and the translational suppressor TIAR, were found to interact specifically with the 3' untranslated region (UTR) of the GADD45alpha mRNA in HeLa cells. These associations were prominent in unstimulated cells, decreasing dramatically after treatment with the genotoxin methyl methanesulfonate (MMS). Analysis of both endogenous and chimeric GADD45alpha mRNA revealed that in untreated cells AUF1 strongly reduced GADD45alpha mRNA stability, whereas TIAR potently inhibited GADD45alpha translation. After genotoxic stress, AUF1 and TIAR dissociated from the GADD45alpha mRNA, thereby allowing coordinated elevations in both GADD45alpha mRNA half-life and translation rate, respectively. We propose that the posttranscriptional derepression of GADD45alpha critically contributes to its potent upregulation after DNA damage.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. ashishl@grc.nia.nih.gov
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Rudolf
authors.initials: R
authors.lastname: Pullmann
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kawai
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galban
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.forename: Gary
authors.initials: G
authors.lastname: Brewer
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D006207:Half-Life; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014176:Protein Biosynthesis; D026721:RNA 3' End Processing; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D008741:Methyl Methanesulfonate; D009153:Mutagens; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C000630986:HNRNPD protein, human; C076751:TIAL1 protein, human