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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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution

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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. AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * The Wistar Institute, Philadelphia, 19104-4268, PA, USA John Bothos, Matthew K Summers, Monica Venere, Daniel M Scolnick & Thanos D Halazonetis * Program in Cell and

Molecular Biology, University of Pennsylvania, Philadelphia, 19104-4268, PA, USA John Bothos, Matthew K Summers & Monica Venere * Program in Biochemistry and Biophysics, Biomedical

Graduate Studies, University of Pennsylvania, Philadelphia, 19104-4268, PA, USA Daniel M Scolnick * Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia,

19104-4268, PA, USA Thanos D Halazonetis Authors * John Bothos View author publications You can also search for this author inPubMed Google Scholar * Matthew K Summers View author

publications You can also search for this author inPubMed Google Scholar * Monica Venere View author publications You can also search for this author inPubMed Google Scholar * Daniel M

Scolnick View author publications You can also search for this author inPubMed Google Scholar * Thanos D Halazonetis View author publications You can also search for this author inPubMed 

Google Scholar CORRESPONDING AUTHOR Correspondence to Thanos D Halazonetis. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 13 January 2003 * Revised: 20 May 2003 * Accepted: 28 May 2003 * Published: 16 October 2003 * Issue Date: 16 October 2003

* DOI: https://doi.org/10.1038/sj.onc.1206831 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * checkpoint * mitosis * ubiquitination * Chfr *

Ubc13