Response to Watts and Saunders: Effects of EDD on p53 Function Are Context-specific

This is a response to a letter by Watts and Saunders (1)

The nice study by Saunders and colleagues does indicate that the role of EDD in extraembryonic development is p53-independent (2). However, we want to draw attention to a new study, which might explain the seemingly conflicting results from HeLa cells (3) compared with those from other cell lines and non-transformed fibroblasts (4). A recent paper by Tomaic et al. (5) demonstrates that EDD directly binds HPV-18 E6/E6AP and inhibits E6 degradation activity. As a result, EDD knockdown in HeLa cells (harboring HPV-18) enhances E6 activity and leads to a striking decrease in the levels of p53 expression and correspondingly a decrease in etoposide-induced apoptosis. Thus, the E6-mediated effects could, at least in part, be responsible for the different outcomes upon EDD depletion in HeLa cells. With the EDD-E6/E6AP regulation, some changes on cell cycle/DNA damage checkpoints following EDD depletion in HeLa cells might be mediated by E6 activation, rather than reflect the physiological function of EDD in normal cells. It is also worth mentioning that we have not been able to observe a consistent change of E2F1 levels following EDD depletion in our cell lines, suggesting that E2F1 may not be regulated directly by EDD.