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

Oncogene volume 30, pages 3073–3083 (2011)Cite this article

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Abstract

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.

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Acknowledgements

We thank Dr JL Manley for anti-CstF2 antibodies, Dr B Vogelstein and Dr J Bargonetti for cell lines DLD-1 and D-A2, Dr EK Boamah for technical advice, Dr C Prives for p53 encoding plasmids, Dr R Baer for BARD1 encoding plasmids and Dr S Piñol-Roma and Dr MA Cevher for advice and discussion. This work is supported by National Institute of General Medical Sciences Grant SC1GM083806 to FEK and by Minority Access to Research Careers Program (MARC) to BA and CT.

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  1. Chemistry Department, Hunter College, City University of New York, New York, NY, USA

    F I Nazeer, E Devany, S Mohammed, D Fonseca, B Akukwe, C Taveras & F E Kleiman

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  1. F I Nazeer
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  2. E Devany
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Correspondence to F E Kleiman.

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Nazeer, F., Devany, E., Mohammed, S. et al. p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex. Oncogene 30, 3073–3083 (2011). https://doi.org/10.1038/onc.2011.29

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