When treated with some DNA-damaging agents, human tumor-derived H1299 cells expressing inducible versions of wild-type or mutant p53 with inactive transactivation domain I (p53(Q22/S23)) undergo apoptosis as evidenced by cytochrome c release, nuclear fragmentation, and sub-G1 DNA content. Apoptosis induced by p53(Q22/S23) is relatively slow, however, and key downstream effector caspases are not activated. Nevertheless, with either version of p53, caspase 2 activation is required for release of cytochrome c and cell death. Remarkably, although p53(Q22/S23) is known to be defective in transcriptional activation of numerous p53 target genes, it can induce expression of proapoptotic targets including PIDD and AIP1 at least to the same extent as wild-type p53. Furthermore, RNAi silencing of PIDD, previously shown to be required for caspase 2 activation, suppresses apoptosis by both wild-type p53 and p53(Q22/S23). Thus, the initial stage of DNA damage-facilitated, p53-mediated apoptosis occurs by a PIDD- and caspase 2-dependent mechanism, and p53's full transcriptional regulatory functions may be required only for events that are downstream of cytochrome c release.