Essential postmitochondrial function of p53 uncovered in DNA damage-induced apoptosis in neurons

In postmitotic sympathetic neurons, unlike most mitotic cells, death by apoptosis requires not only the release of cytochrome c from the mitochondria, but also an additional step to relieve X- linked inhibitor of apoptosis protein ( XIAP)' s inhibition of caspases. Here, we examined the mechanism by which XIAP is inactivated following DNA damage and found that it is achieved by a mechanism completely different from that following apoptosis by nerve growth factor ( NGF) deprivation. NGF deprivation relieves XIAP by selectively degrading it, whereas DNA damage overcomes XIAP via a p53- mediated induction of Apaf- 1. Unlike wild- type neurons, p53- deficient neurons fail to overcome XIAP and remain resistant to cytochrome c after DNA damage. Restoring Apaf- 1 induction in p53- deficient neurons is sufficient to overcome XIAP and sensitize cells to cytochrome c. Although a role for p53 in apoptosis upstream of cytochrome c release has been well established, this study uncovers an additional, essential role for p53 in regulating caspase activation downstream of mitochondria following DNA damage in neurons.