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The tumor suppressor p53 associates with gene coding regions and co-traverses with elongating RNA polymerase II in an in vivo model

Oncogene volume 27, pages 2661–2672 (2008)Cite this article

Abstract

Sequence-specific transcriptional regulators function by stably binding cognate DNA sequences followed by recruitment of both general and specialized factors to target gene promoters. The tumor suppressor p53 mediates its anti-oncogenic effect on cells by functioning as a sequence-specific regulator. p53 employs a secondary mechanism to suppress tumor formation by permeabilizing the outer mitochondrial membrane, thereby releasing pro-apoptotic factors. Here, we report a potential third biological function of p53: as a transcriptional elongation factor. Using chromatin immunoprecipitation, we demonstrate that human p53 robustly associates with RNA polymerase II (Pol II), but neither Pol I- nor Pol III-transcribed regions in the budding yeast, Saccharomyces cerevisiae. p53's association with open reading frames is mediated by its physical interaction with elongating Pol II, with which p53 travels in vivo and co-immunoprecipitates in vitro. When similarly expressed, the potent acidic activator VP16 cannot be cross-linked to Pol II coding regions. p53 levels comparable to those found in induced mammalian cells confer synthetic sickness or lethality in combination with deletions in genes encoding transcription elongation factors; p53 likewise confers hypersensitivity to the anti-elongation drug 6-azauracil. Collectively, our results indicate that p53 can physically interact with the transcription elongation complex and influence transcription elongation, and open up new avenues of investigation in mammalian cells.

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Acknowledgements

We thank Yoshi Odaka, Jorge Herrera-Diaz, David Chiluiza and Jing Zhao for technical assistance; Bert Vogelstein, David Bentley, Jef Boeke, Charles Di Como, Michael Green, Shile Huang, Jennifer Larson, Francesc Posas, Carol Prives, Kelly Tatchell and Fred Winston for gifts of plasmids, yeast strains, antibodies and mammalian cell lines; Alex Erkine for sharing unpublished genomic footprinting data and Mike Hampsey and Neal Mathias for critical reading of an earlier version of the manuscript. This work was supported by grants from the Feist-Weiller Cancer Center and the National Science Foundation (MCB-0450419).

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  1. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center and The Feist-Weiller Cancer Center, Shreveport, LA, USA

    S K Balakrishnan & D S Gross

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  1. S K Balakrishnan
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  2. D S Gross
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Correspondence to D S Gross.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Balakrishnan, S., Gross, D. The tumor suppressor p53 associates with gene coding regions and co-traverses with elongating RNA polymerase II in an in vivo model. Oncogene 27, 2661–2672 (2008). https://doi.org/10.1038/sj.onc.1210935

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