The tumor suppressor p53 is a critical component of the DNA damage response pathway that induces a set of genes responsible for cell cycle arrest, senescence, apoptosis, and DNA repair. The ataxia telangiectasia mutated protein kinase (ATM) responds to DNA-damage stimuli and signals p53 stabilization and activation, thereby facilitating transactivation of p53 inducible genes and maintainence of genome integrity. In this study, we identified a CXXC zinc finger domain containing protein termed CF5 as a critical component in the DNA damage signaling pathway. CF5 induces p53 transcriptional activity and apoptosis in cells expressing wild type p53 but not in p53-deficient cells. Knockdown of CF5 inhibits DNA damage-induced p53 activation as well as cell cycle arrest. Furthermore, CF5 physically interacts with ATM and is required for DNA damage-induced ATM phosphorylation but not its recruitment to chromatin. These findings suggest that CF5 plays a crucial role in ATM-p53 signaling in response to DNA damage.