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The E3 Ubiquitin Ligase EDD Regulates S-Phase and G₂/M DNA Damage Checkpoints

Marcia A. Munoz, Darren N. Saunders, Michelle J. Henderson, Jennifer L. Clancy, Amanda J. Russell, Gillian Lehrbach, Elizabeth A. Musgrove, Colin K.W. Watts and Robert L. Sutherland

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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 G1/S and intra S phase DNA damage checkpoint activation and for the maintenance of G2/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.

Authors

Marcia A. Munoz

Garvan Institute of Medical Research; Darlinghurst, Australia

Darren N. Saunders

Garvan Institute of Medical Research; Darlinghurst, Australia

Michelle J. Henderson

Garvan Institute of Medical Research; Darlinghurst, Australia

Jennifer L. Clancy

Garvan Institute of Medical Research; Darlinghurst, Australia

Amanda J. Russell

Garvan Institute of Medical Research; Darlinghurst, Australia

Gillian Lehrbach

Garvan Institute of Medical Research; Darlinghurst, Australia

Elizabeth A. Musgrove

Cancer Research Program, Garvan Institute of Medical Research

Colin K.W. Watts

Garvan Institute of Medical Research; Darlinghurst, Australia

Robert L. Sutherland

Garvan Institute of Medical Research; Darlinghurst, Australia

Purchase article for $19

Subscribe to this journal for $129/year