Posttranscriptional Derepression of GADD45α by Genotoxic Stress

SummaryThe growth arrest- and DNA damage-inducible gene GADD45α 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 GADD45α 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 GADD45α mRNA revealed that in untreated cells AUF1 strongly reduced GADD45α mRNA stability, whereas TIAR potently inhibited GADD45α translation. After genotoxic stress, AUF1 and TIAR dissociated from the GADD45α mRNA, thereby allowing coordinated elevations in both GADD45α mRNA half-life and translation rate, respectively. We propose that the posttranscriptional derepression of GADD45α critically contributes to its potent upregulation after DNA damage.