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Vol. 18, Issue 9, 3340-3350, September 2007

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Cdc6 Stability Is Regulated by the Huwe1 Ubiquitin Ligase after DNA Damage

Jonathan R. Hall^*, Evelyn Kow^,, Kathleen R. Nevis^*, Chiajung Karen Lu, K. Scott Luce^*, Qing Zhong, and Jeanette Gowen Cook^*

*Department of Biochemistry and Biophysics, School of Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7260; Department of Molecular Genetics, Duke University Medical Center, Durham, NC 27710; and Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3204

Submitted February 26, 2007; Revised May 9, 2007; Accepted June 6, 2007
Monitoring Editor: Orna Cohen-Fix

The Cdc6 protein is an essential component of pre-replication complexes (preRCs), which assemble at origins of DNA replication during the G1 phase of the cell cycle. Previous studies have demonstrated that, in response to ionizing radiation, Cdc6 is ubiquitinated by the anaphase promoting complex (APC^Cdh1) in a p53-dependent manner. We find, however, that DNA damage caused by UV irradiation or DNA alkylation by methyl methane sulfonate (MMS) induces Cdc6 degradation independently of p53. We further demonstrate that Cdc6 degradation after these forms of DNA damage is also independent of cell cycle phase, Cdc6 phosphorylation of the known Cdk target residues, or the Cul4/DDB1 and APC^Cdh1 ubiquitin E3 ligases. Instead Cdc6 directly binds a HECT-family ubiquitin E3 ligase, Huwe1 (also known as Mule, UreB1, ARF-BP1, Lasu1, and HectH9), and Huwe1 polyubiquitinates Cdc6 in vitro. Degradation of Cdc6 in UV-irradiated cells or in cells treated with MMS requires Huwe1 and is associated with release of Cdc6 from chromatin. Furthermore, yeast cells lacking the Huwe1 ortholog, Tom1, have a similar defect in Cdc6 degradation. Together, these findings demonstrate an important and conserved role for Huwe1 in regulating Cdc6 abundance after DNA damage.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-02-0173) on June 13, 2007.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present address: The Johns Hopkins Hospital, Room 100, Tower Building, Baltimore, MD 21287.

Address correspondence to: Jeanette Gowen Cook (jean_cook{at}med.unc.edu).

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