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  • Original Article
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K63-Ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair

Oncogene volume 33, pages 1055–1065 (2014)Cite this article

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Abstract

DNA repair is essential for maintaining genomic stability, and defects in this process significantly increase the risk of cancer. Clear-cell renal cell carcinoma (CCRCC) caused by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is characterized by high genomic instability. However, the molecular mechanism underlying the association between the loss of VHL and genomic instability remains unclear. Here, we show that suppressor of cytokine signaling 1 (SOCS1) promotes nuclear redistribution and K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs). Loss of VHL or VHL mutations that compromise its K63-ubiquitylation attenuates the DNA-damage response (DDR), resulting in decreased homologous recombination repair and persistence of DSBs. These results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC.

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Acknowledgements

This work was supported by funds from the Canadian Institutes of Health Research (MOP77718).

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    J L Metcalf, S N Greer & M Ohh

  2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    P S Bradshaw & M Stephen Meyn

  3. Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

    M Komosa & M Stephen Meyn

  4. Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

    M Stephen Meyn

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  1. J L Metcalf
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Correspondence to M Ohh.

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Metcalf, J., Bradshaw, P., Komosa, M. et al. K63-Ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. Oncogene 33, 1055–1065 (2014). https://doi.org/10.1038/onc.2013.22

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