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p53 regulates its own expression by an intrinsic exoribonuclease activity through AU-rich elements

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Abstract

The onco-suppressor p53 protein plays also an important role in the control of various aspects of health and disease. p53 levels are low in normal cells and elevated under stress conditions. While low levels of p53 promote tumor formation, overactive p53 leads to premature aging and cell death. RNA degradation is a critical level of regulation contributing to the control of gene expression. p53, as an RNA-binding protein, exerts 3′ → 5′ exoribonuclease activity, mediating degradation of adenylate/uridylate-rich elements (ARE)–containing ssRNAs. The 3′-UTR of p53-mRNA, which is a target of p53 itself, harbors cis-acting AREs. Our results suggest that p53 controls its own expression through murine double-minute 2 (mdm2)–independent “RNA decay” function in cytoplasm. We demonstrate that p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA via translation-independent and translation-dependent polysome-associated pathways. Antagonistic interplay was detected between p53 levels and execution of its exoribonuclease function mirrored in low p53 levels in normal cells, due to the efficient exoribonuclease activity, and in the accumulation of p53 in cells exposed to p53-activating drugs in accordance with the reduced exoribonuclease activity. Apparently, p53, via control of its own mRNA stability and/or translation in cytoplasm, might act as a negative regulator of p53-mRNA levels. The observed connection between exoribonuclease activity and p53 abundance highlights the importance of this function affecting p53 expression, imperative for multiple functions, with implications for the steady-state levels of protein and for the p53 stress response. The modulation in expression of exoribonuclease activity would be translated into the alterations in p53 level.

Key messages

  • p53 controls its own expression through mdm2-independent “RNA decay” function in cytoplasm.

  • p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA.

  • Antagonistic interplay exists between stress-induced p53 and execution of its exoribonuclease function.

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Acknowledgments

MDA-MB-468 cells were provided by Prof. R. Yerushalmi from Rabin Medical Center, Davidoff Cancer Center, Petach Tiqva, Israel. HCT116 isogenic cells were provided by Prof. M. Oren from Weizmann Institute, Rechovot, Israel.

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Authors and Affiliations

  1. Infectious Diseases Unit, Sheba Medical Center, 5265601, Tel-Hashomer, Israel

    Sanaz Derech-Haim & Mary Bakhanashvili

  2. The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel

    Yael Friedman & Mary Bakhanashvili

  3. Department of Cellular and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Amnon Hizi

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  1. Sanaz Derech-Haim
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  2. Yael Friedman
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  4. Mary Bakhanashvili
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Contributions

S.D. and Y.F. performed the experiments; A.H. reviewed the results and thoroughly edited the manuscript; M.B. designed the study and wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Mary Bakhanashvili.

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Derech-Haim, S., Friedman, Y., Hizi, A. et al. p53 regulates its own expression by an intrinsic exoribonuclease activity through AU-rich elements. J Mol Med 98, 437–449 (2020). https://doi.org/10.1007/s00109-020-01884-0

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  • DOI: https://doi.org/10.1007/s00109-020-01884-0

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