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Chfr Regulates a Mitotic Stress Pathway through its RING-Finger Domain with Ubiquitin Ligase Activity¹

Departments of Oncology Research [P. C., M. L. B., P. W. F., M. R. M., B-B. S. Z.], Bioinformatics [M. R. H.], and Molecular Biology [Y. Z.], GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, and Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [V. S., S. A. J., T. J. Y.]

Resistance to chemotherapy targeting microtubules could be partially because of the delay in chromosome condensation and segregation during mitosis. The Chfr pathway has been defined recently, and its activation causes a delay in chromosome condensation in response to mitotic stress. Because Chfr contains a RING-finger domain, we tested whether Chfr inhibits chromosome condensation through an ubiquitin (ubiquitin)-dependent pathway. In the presence of purified E1, Ubc4, or Ubc5, and ubiquitin, Chfr catalyzes its own ubiquitination in vitro, an activity requiring the RING domain. In vivo, overexpressed Chfr but not a RING domain mutant is spontaneously ubiquitinated. Our studies with DLD1 cells stably expressing wild-type Chfr and Chfr lacking the RING domain indicated that the RING-finger deletion mutant was defective in inhibiting chromosome condensation after Taxol treatment. In addition, Chfr expression increases the survival rate after Taxol treatment, an activity requiring the RING domain. Preliminary studies indicate that Chfr expression is cell cycle regulated and is dependent on its ubiquitin ligase activity. It is very likely that the Chfr-mediated ubiquitin-dependent pathway is a critical component of the response to mitotic stress.

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