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The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains

Oncogene volume 22, pages 7101–7107 (2003)Cite this article

Abstract

We recently described a novel checkpoint pathway that functions early in mitosis to delay chromosome condensation in response to microtubule poisons. The only gene implicated so far in this checkpoint pathway is chfr, whose protein product contains a RING domain and has ubiquitin ligase activity in vitro. The significance of this activity in vivo is unclear. A recent report suggested that the Chfr protein targets itself for proteasome-dependent degradation in mitotic cells through autoubiquitination. However, we observe that in mitosis Chfr exhibits a phosphorylation-dependent electrophoretic mobility shift with no change in overall protein levels. Further analysis of its ubiquitin ligase activity revealed that Chfr can catalyse the formation of noncanonical Lys63-linked polyubiquitin chains with Ubc13-Mms2 acting as the ubiquitin-conjugating enzyme. Ubc13-Mms2 and Lys63-polyubiquitin chains are not associated with targeting proteins to the proteasome, but rather with signaling cellular stress. We propose that Chfr may have a role in signaling the presence of mitotic stress induced by microtubule poisons.

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Acknowledgements

We thank Peter Howley for the gift of plasmids expressing wheat E1, UbcH7 and UbcH8 and Frank Rauscher III and Philip Leder for their support and helpful discussions. This study was supported in part by the National Cancer Institute Grant CA89630 (to TDH); JB and MS were supported by National Cancer Institute Training Grants CA09171 and CA09677, respectively.

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Authors and Affiliations

  1. The Wistar Institute, Philadelphia, 19104-4268, PA, USA

    John Bothos, Matthew K Summers, Monica Venere, Daniel M Scolnick & Thanos D Halazonetis

  2. Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, 19104-4268, PA, USA

    John Bothos, Matthew K Summers & Monica Venere

  3. Program in Biochemistry and Biophysics, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, 19104-4268, PA, USA

    Daniel M Scolnick

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104-4268, PA, USA

    Thanos D Halazonetis

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  1. John Bothos
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Correspondence to Thanos D Halazonetis.

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Bothos, J., Summers, M., Venere, M. et al. The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains. Oncogene 22, 7101–7107 (2003). https://doi.org/10.1038/sj.onc.1206831

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