An intact cellular response to DNA damage is important for the maintenance of genomic stability and tumour prevention. EDD, the human orthologue of Drosophila melanogaster ???hyperplastic discs???, is over-expressed or mutated in a number of common human cancers. EDD is a progestin regulated gene that encodes an E3 ubiquitin ligase involved in cell communication and cell adhesion, and although it has also been implicated in the DNA damage response through its association with DNA damage proteins, a definitive role has yet to be demonstrated. The work presented herein shows that EDD is necessary for an adequate cellular response to double-strand DNA breaks. Cells depleted of EDD exhibit reduced survival, radio-resistant DNA synthesis and failure to maintain G2/M arrest following DNA damage induced by phleomycin exposure. Furthermore, EDD-depleted cells display impaired activating phosphorylation and kinase activity of the checkpoint kinase CHK2 after DNA damage. These effects appear to be largely modulated through a phospho-dependent interaction involving the CHK2 FHA domain and a region of EDD spanning a number of putative FHA-binding threonines. These results identify EDD as a novel mediator in DNA damage signal transduction via CHK2 and emphasise the potential importance of EDD in cancer.
| Identifer | oai:union.ndltd.org:ADTP/215415 |
| Date | January 2006 |
| Creators | Munoz, Marcia, Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Medicine |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Marcia Munoz, http://unsworks.unsw.edu.au/copyright |
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