Endogenous Antisense Increases p53

Science Signaling  03 Mar 2009:
Vol. 2, Issue 60, pp. ec79
DOI: 10.1126/scisignal.260ec79

The tumor suppressor p53 is important for the cellular response to DNA damage and is encoded by one of the most frequently mutated genes in cancer cells. The regulation of p53 abundance is complex, with transcriptional and posttranscriptional mechanisms playing important roles. Mahmoudi et al. identified an antisense transcript that overlaps with the first exon of p53 and that, when knocked down, decreases the abundance of both p53 transcript and protein. They called the antisense transcript Wrap53, for WD40-encoding RNA antisense to p53, and showed that the p73 gene also had an overlapping Wrap73 antisense gene. Various techniques were used to verify that the increase in p53 did not require the Wrap53 protein. For example, silencing RNAs (siRNAs) targeted specifically to the exon 1α (a transcript from the alternative start site that is the only Wrap53 transcript that overlaps with the p53 coding sequence) decreased p53 abundance without affecting Wrap53 protein abundance, and overexpression of only the exon 1α, which does not encode protein, increased p53 abundance. Wrap53 and the corresponding region of the p53 gene appeared to form a duplex, and inhibition of this duplex by the introduction of 2′-O-methyl oligoribonucleotides reduced p53 abundance. The importance of Wrap53 regulation of p53 in the response to DNA damage was evident by the reduced stimulation in p53 in cells exposed to DNA-damaging agents that were also depleted for Wrap53, and overexpression of a truncated Wrap53 that included the exon 1α increased DNA damage–induced cell death.

S. Mahmoudi, S. Henriksson, M. Corcoran, C. Méndez-Vidal, K. G. Wiman, M. Farnebo, Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol. Cell 33, 462–471 (2009). [PubMed]