p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

The mechanisms involved in the p53-dependent control of gene expression following DNA damage have not been completely elucidated. Here, we show that the p53 C terminus associates with factors that are required for the ultraviolet (UV)-induced inhibition of the mRNA 3′ cleavage step of the polyadenylation reaction, such as the tumor suppressor BARD1 and the 3′ processing factor cleavage-stimulation factor 1 (CstF1). We found that p53 can coexist in complexes with CstF and BARD1 in extracts of UV-treated cells, suggesting a role for p53 in mRNA 3′ cleavage following DNA damage. Consistent with this, we found that p53 inhibits 3′ cleavage in vitro and that there is a reverse correlation between the levels of p53 expression and the levels of mRNA 3′ cleavage under different cellular conditions. Supporting these results, a tumor-associated mutation in p53 not only decreases the interaction with BARD1 and CstF, but also decreases the UV-induced inhibition of 3′ processing, all of which is restored by wild-type-p53 expression. We also found that p53 expression levels affect the polyadenylation levels of housekeeping genes, but not of p21 and c-fos genes, which are involved in the DNA damage response (DDR). Here, we identify a novel 3′ RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network.