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Modulation of microRNA processing by p53

Nature volume 460, pages 529–533 (2009)Cite this article

Abstract

MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development1, a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis2,3,4. This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.

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Figure 1: Post-transcriptional modification of miRNA biogenesis by p53 and p68/p72 in response to DNA damage.
Figure 2: Association between p53 and Drosha complex.
Figure 3: p53 facilitates Drosha-mediated pri-miRNA processing.
Figure 4: Deregulation of miRNA processing by mutant p53.

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Acknowledgements

We thank H. Matsuyama, K. Kiyono, S. Ehata and R. A. Saito for discussion; M. Saitoh, K. Miyazawa, T. Watabe, K. Horiguchi, T. Shirakihara, K. Harada, M. Oka, A. Mizutani, T. Yamazaki and Y. Yoshimatsu for technical advice and reagents; T. Yokochi and Y. Morishita for encouragement; and all members of the Department of Molecular Pathology, University of Tokyo for assistance. This work was supported by KAKENHI (Grant-in-Aid for Scientific Research no. 17016011) on priority areas ‘New strategies for cancer therapy based on advancement of basic research’ and the Global Center of Excellence Program for ‘Integrative Life Science Based on the Study of Biosignaling Mechanisms’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan. H.I.S. is supported by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists.

Author Contributions H.I.S. conceived and designed the research, performed experiments and analyses and wrote the paper. Y.K., T.I. and S.K. provided key materials. K.S. and K.M. supervised the whole project and wrote the paper.

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Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,

    Hiroshi I. Suzuki & Kohei Miyazono

  2. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan ,

    Kaoru Yamagata & Shigeaki Kato

  3. ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan ,

    Kaoru Yamagata & Shigeaki Kato

  4. Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan,

    Koichi Sugimoto

  5. The Center for Education in Laboratory Animal Research and Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan,

    Takashi Iwamoto

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  1. Hiroshi I. Suzuki
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Correspondence to Kohei Miyazono.

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Suzuki, H., Yamagata, K., Sugimoto, K. et al. Modulation of microRNA processing by p53. Nature 460, 529–533 (2009). https://doi.org/10.1038/nature08199

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