PIDDosome is a recently-identified caspase-2-activating molecular complex formed by genotoxic stress that leads to caspase-2-dependent apoptosis. PIDD, RAIDD, and caspase-2 are three protein components of PIDDosome. The core portion of PIDDosome is formed by the unique screw rotation of seven RAIDD DD and five PIDD DD. In the current study, we found that two mutations generated during structural-based mutagenesis studies, Q169E and R170A on RAIDD DD, were dominant negative. Because the discovery of dominant-negative mutants might implicate the disease and therapeutic intervention, newly identified dominant-negative mutants could lead to new potential applications for treatment of human diseases caused by excessive or reduced apoptosis.