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, Jeanette Gowen Cook

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

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 APCCdh1 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 Huwel ortholog, Tom1, have a similar defect in Cdc6 degradation. Together, these findings demonstrate an important and conserved role for Huwel in regulating Cdc6 abundance after DNA damage.

Original languageEnglish (US)
Pages (from-to)3340-3350
Number of pages11
JournalMolecular biology of the cell
Volume18
Issue number9
DOIs
StatePublished - Sep 1 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hall, J. R., Kow, E., Nevis, K. R., Lu, C. K., Luce, K. S., Zhong, Q., & Cook, J. G. (2007). Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Molecular biology of the cell, 18(9), 3340-3350. https://doi.org/10.1091/mbc.E07-02-0173