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The ribosomal protein S26 regulates p53 activity in response to DNA damage

Oncogene volume 33, pages 2225–2235 (2014)Cite this article

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Abstract

Ribosomal proteins have emerged as novel regulators of the Mdm2-p53 feedback loop, especially in the context of ribosomal stress. RPS26 is a recently identified Diamond-Blackfan Anemia-related ribosomal protein and its role in p53 activation has not been previously explored. In this study we found knockdown of RPS26 induced p53 stabilization and activation via a RPL11-dependent mechanism, resulting in p53-dependent cell growth inhibition. Moreover, RPS26 has the ability to interact with Mdm2 and inhibits Mdm2-mediated p53 ubiquitination that leads to p53 stabilization upon overexpression. Importantly, we discovered that RPS26 knockdown impaired p53’s ability to transcriptionally activate its target genes in response to DNA damage, without affecting its stability. Accordingly, the cells lost the ability to induce G2/M cell cycle arrest. We further found that upon RPS26 knockdown, the DNA damage induced recruitment of p53 to the promoters of its target genes and p53 acetylation were both greatly reduced. In addition, RPS26 can interact with p53 independent of Mdm2 and coexist in a complex with p53 and p300. These data establish a role of RPS26 in DNA damage response by directly influencing p53 transcriptional activity, and suggest that RPS26 acts distinctively in different scenarios of p53 activation. Our finding also implicates p53 transcriptional activity control as an important mechanism of p53 regulation by ribosomal proteins.

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Acknowledgements

We thank Dr Xiaolu Yang for generously providing constructs and reagents; Dr Weiguo Zhu for providing the Ha-p300 expression plasmid; Yongqiang Wang for technical assistance; Dr Julia Hill for critically reading the manuscript and Caroline Kitzmiller for proofreading the manuscript. This work was supported by the National Natural Science Foundation of China (31171331); the Program for New Century Excellent Talents in University of China (NCET-09-0737) and the research fund from the State Key Laboratory of Agrobiotechnology of China (2010SKLAB06-5).

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Authors and Affiliations

  1. State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China

    D Cui, L Li, H Lou, H Sun & J Tang

  2. Department of Basic Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, China

    D Cui, L Li, H Sun & J Tang

  3. College of Biological Sciences, China Agricultural University, Beijing, China

    H Lou

  4. Department of Biology and State (China) Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China

    S-M Ngai

  5. Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    G Shao

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Cui, D., Li, L., Lou, H. et al. The ribosomal protein S26 regulates p53 activity in response to DNA damage. Oncogene 33, 2225–2235 (2014). https://doi.org/10.1038/onc.2013.170

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