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J Biol Chem, Vol. 274, Issue 26, 18785-18792, June 25, 1999
From the Harvard Medical School, Department of Pathology,
Boston, Massachusetts 02115
The human papilloma virus E6-associated protein
(E6AP) functions as a ubiquitin protein ligase (E3) in the E6-mediated
ubiquitination of p53. E6AP is also an E3 in the absence of E6, but its
normal cellular substrates have not yet been identified. Here we report the identification of HHR23A, one of the human homologues of the yeast
DNA repair protein Rad23, as an E6-independent target of E6AP. HHR23A
binds E6AP and is ubiquitinated in vitro in an
E6AP-dependent manner. Ubiquitinated forms of endogenous
HHR23A are detectable in mammalian cells. Overexpression of wild-type
E6AP in vivo enhances the ubiquitination of HHR23A, whereas
a dominant negative E6AP mutant inhibits HHR23A ubiquitination.
Although HHR23A is a stable protein in non-synchronized cells, its
levels are regulated in a cell cycle-dependent manner, with
specific degradation occurring during S phase. The S phase degradation
of HHR23A could be blocked in vivo by dominant negative
E6AP, providing direct evidence for the involvement of E6AP in the
regulation of HHR23A. Consistent with a role of the HHR23 proteins in
DNA repair, UV-induced DNA damage inhibited HHR23A degradation.
Although the precise role of HHR23 proteins in DNA repair and cell
cycle progression remains to be elucidated, our data suggest that
E6AP-mediated ubiquitination of HHR23A may have important implications
in DNA repair and cell cycle progression.
Identification of HHR23A as a Substrate for E6-associated
Protein-mediated Ubiquitination
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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