The tumor suppressor p53 is pivotal in cell growth arrest and apoptosis upon cellular stresses including DNA damage. Mounting evidence indicates that p63 proteins, which are homologs of p53, are also involved in apoptosis under certain circumstances. In this study, we found that treatment with DNA damage agents leads to down-regulation of Delta Np63 alpha and induces apoptosis in FaDu and HaCat cells carrying mutant p53. Further study shows that DNA damage reduces steady-state mRNA level of Delta Np63 alpha, but has little effect on its protein stability. In addition, knockdown of endogenous Delta Np63 alpha directly induces apoptosis and sensitizes cells to DNA damage, while exogenous expression of Delta Np63 alpha partially confers cellular resistance to DNA damage. Together, these data suggest that DNA damage down-regulates Delta Np63 alpha, which may directly contribute to DNA damage-induced apoptosis. (C) 2012 Elsevier Inc. All rights reserved.