Posttranscriptional derepression of GADD45α by genotoxic stress

The growth arrest- and DNA damage-inducible gene GADD45 alpha 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 GADD45 alpha 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 GADD45 alpha mRNA revealed that in untreated cells AUF1 strongly reduced GADD45 alpha mRNA stability, whereas TIAR potently inhibited GADD45 alpha translation. After genotoxic stress, AUF1 and TIAR dissociated from the GADD45 alpha mRNA, thereby allowing coordinated elevations in both GADD45 alpha mRNA half-life and translation rate, respectively. We propose that the posttranscriptional derepression of GADD45 alpha critically contributes to its potent upregulation after DNA damage.