The E3 ubiquitin ligase EDD regulates S-phase and G(2)/M DNA damage checkpoints.
The cellular response to DNA damage is critical for maintenance of genomic integrity and inhibition of tumorigenesis. Mutations or aberrant expression of the E3 ubiquitin ligase EDD have been observed in a number of carcinomas and we recently reported that EDD modulates activity of the DNA damage checkpoint kinase, CHK2. Here, we demonstrate that EDD is necessary for G(1)/S and intra S phase DNA damage checkpoint activation and for the maintenance of G(2)/M arrest after double strand DNA breaks. Defective checkpoint activation in EDD-depleted cells led to radio-resistant DNA synthesis, premature entry into mitosis, accumulation of polyploid cells, and cell death via mitotic catastrophe. In addition to decreased CHK2 activation in EDD-depleted cells, the expression of several key cell cycle mediators including Cdc25A/C and E2F1 was altered, suggesting that these checkpoint defects may be both CHK2-dependent and -independent. These data support a role for EDD in the maintenance of genomic stability, emphasising the potential importance of dysregulated EDD expression and/or function in the evolution of cancer.
Munoz
Marcia A
MA
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Saunders
Darren N
DN
Henderson
Michelle J
MJ
Clancy
Jennifer L
JL
Russell
Amanda J
AJ
Lehrbach
Gillian
G
Musgrove
Elizabeth A
EA
Watts
Colin K W
CK
Sutherland
Robert L
RL
D018797:Cell Cycle Proteins / Q000502:physiology; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000502:physiology*; D016195:G2 Phase / Q000502:physiology*; D042822:Genomic Instability / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016196:S Phase / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D018797:Cell Cycle Proteins; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases