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K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay

Oncogene volume 38, pages 1597–1610 (2019)Cite this article

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Abstract

The point mutation that substitutes lysine with arginine at position 120 of human p53 has been characterized as a missense mutation. The K120R mutation renders the p53 protein disabled for acetylation and, as a result, defective for apoptotic function, which provides a mechanistic link between the missense mutation and tumorigenesis. However, we noticed the failures of tumorigenesis in mice with the mutation, and of the related studies to notice that it has arbitrarily reflected in amino acid change through a sequence modification (AGA) of the original tumor mutation (AGG) by codon degeneracy. Unlike this modified version, we also discovered a novel splicing site the original mutation, TP53 c.359A>G, may induce. Using a human induced pluripotent stem cell line that was engineered to be homozygous for the original mutation, we here identified that the accidental splicing site generates a defective transcript variant with a frame-shifted premature termination codon which is subjected to nonsense-mediated mRNA decay. The authentic splicing still occurs but in extremely low amounts. Taken together, this mutation causes depletion of cellular p53 via defective mRNA, suggesting a new link to tumorigenesis.

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Acknowledgements

We thank B-J. Park, K-S. Chae, and I. Horikawa for comments on the manuscript and Y-D. Kim for technical assistance. This research was supported in part by the National Research Foundation of Korea Grants (NRF-2013M3A9B4076487) and Korea Institute of Oriental Medicine Grants (K18131).

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Authors and Affiliations

  1. Division of Clinical Medicine, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, South Korea

    Seo-Young Lee, Jung-Hyun Park, Sangkyun Jeong, Bu-Yeo Kim & Sun-Ku Chung

  2. Development and Differentiation Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea

    Yong-Kook Kang

  3. Department of Functional Genomics, Korea University of Science and Technology, Daejeon, South Korea

    Yong-Kook Kang

  4. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0322, USA

    Yang Xu

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  1. Seo-Young Lee
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Correspondence to Sun-Ku Chung.

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Lee, SY., Park, JH., Jeong, S. et al. K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay. Oncogene 38, 1597–1610 (2019). https://doi.org/10.1038/s41388-018-0542-3

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