Another way Wip1 may promote tumorigenesis is through inhibition of gamma-H2AX and the DDR. Through its role in the DDR, gamma-H2AX also plays an important role in tumorigenesis (58). The DDR acts as a barrier to oncogenic transformation and is triggered after oncogenic stress (15, 16). As discussed in section 4.2, Wip1 dephosphorylates gamma-H2AX after genotoxic stress. Our group also showed that Wip1 reduced gamma-H2AX levels in cells experiencing oncogenic stress (7). Wild-type MEFs transformed with E1A and Ras exhibited a limited number of gamma-H2AX foci. However, Wip1−/− MEFs transformed with E1A and Ras exhibited a much larger number of basal gamma-H2AX foci (7). Furthermore, gamma-H2AX levels remained high in Wip1−/− E1A/Ras MEFs compared to wild-type E1A/Ras MEFs after IR exposure. Wip1 dephosphorylation of gamma-H2AX, therefore, may be a mechanism by which Wip1 promotes genomic instability, facilitates cellular transformation, and promotes tumorigenesis.
