The role of mRNA decay in p53-induced gene expression

The p53 tumor suppressor is a DNA damage responsive sequence-specific transcriptional activator. The sustained activation of the p53 response is incompatible with cell growth and viability. To circumvent this issue, a variety of negative feedback loops exist to limit the duration of p53 activation. Despite our understanding of p53-regulation, very little is known about the effect of transient p53 activation on the long term expression of p53 target genes. Here we used a temperature sensitive variant of p53 and oligonucleotide microarrays to monitor gene expression during and following reversible p53 activation. The expression of most p53-induced transcripts was rapidly reversible, consistent with active mRNA decay. Representative 3UTRs derived from short-lived transcripts (i.e. DDB2 and GDF15) conferred instability on a heterologous mRNA while 3UTRs derived from more stable transcripts (i.e. CRYAB and TP53I3) did not. The 3UTRs derived from unstable p53-induced mRNAs were significantly longer than those derived from stable mRNAs. These 3UTRs had high uridine and low cytosine content, leading to a higher density of U-, AU- and GU-rich sequences. Remarkably, short-lived p53 targets were induced faster reaching maximum transcript levels earlier than the stable p53-targets. Taken together, the p53 transcriptional response has evolved with primarily short-lived target mRNAs and that post-transcription processes play a prominent role in the p53 response.

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Melanson BD, Bose R, Hamill JD, Marcellus KA, Pan EF, McKay BC