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Plk1-mediated stabilization of 53BP1 through USP7 regulates centrosome positioning to maintain bipolarity

Oncogene volume 36, pages 966–978 (2017)Cite this article

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Abstract

Although 53BP1 has been established well as a mediator in DNA damage response, its function in mitosis is not clearly understood. We found that 53BP1 is a mitotic-binding partner of the kinases Plk1 and AuroraA, and that the binding with Plk1 increases the stability of 53BP1 by accelerating its interaction with the deubiquitinase USP7. Depletion of 53BP1 induces mitotic defects such as chromosomal missegregation, misorientation of spindle poles and the generation of extra centrosomes, which is similar phenotype to USP7-knockdown cells. In addition, 53BP1 depletion reduces the levels of p53 and centromere protein F (CENPF), interacting proteins of 53BP1. These phenotypes induced by 53BP1 depletion were rescued by expression of wild-type or phosphomimic mutant 53BP1 but not by expression of a dephosphomimic mutant. We propose that phosphorylation of 53BP1 at S380 accelerates complex formation with USP7 and CENPF to regulate their stability, thus having a crucial role in proper centrosome positioning, chromosomal alignment, and centrosome number.

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Acknowledgements

We thank Dr Phillip B Carpenter (University of Texas Health Sciences Center, TX, USA), Dr Stephen J Elledge (Harvard University, MA, USA), Dr Daniel Durocher (University of Toronto, Canada) and Dr Anindya Dutta (University of Virginia School of Medicine, VA, USA) for generously providing plasmids for HA-53BP1, GFP-53BP1 and USP7, respectively. We thank Dr Jeong-Ho Hong (Korea University, Korea), Dr Mi-Ran Byun, Mi Kyung Sung and Hay Ran Jang (Hanyang University, Korea) for technical assistance. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2012R1A2A2A06044458; NRF-2014R1A2A1A11049701) to HY.

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  1. H Yim and S-B Shin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Korea

    H Yim, S-B Shin & S U Woo

  2. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA

    H Yim & R L Erikson

  3. Department of Biomedical Sciences, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea

    P C-W Lee

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Correspondence to H Yim.

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Yim, H., Shin, SB., Woo, S. et al. Plk1-mediated stabilization of 53BP1 through USP7 regulates centrosome positioning to maintain bipolarity. Oncogene 36, 966–978 (2017). https://doi.org/10.1038/onc.2016.263

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