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Tumor suppressor p53 restricts the proliferation of abnormal or DNA-damaged cells by regulating the expression of various genes that are involved in cell cycle arrest,DNA repair,and apoptosis.The selective regulation of p53 target genes is partially achieved through interaction between p53 and its regulators.Only a few p53 regulators have been shown to participate in selective control of p53-mediated cell cycle arrest or apoptosis.How p53-mediated apoptosis is negatively regulated remains largely unclear.We recently identified Apak (ATM and p53 associated KZNF protein),a KRAB-type zinc-finger protein (KZNF),functions as such a role.In unstressed cells,Apak directly binds to p53,specifically downregulates proapoptotic genes,and remarkably suppresses p53-mediated apoptosis.Apak regulates the transcriptional activity of p53 by recruiting KAP-1 (KR-AB.-box-associated protein-1) and HDAC1 (histone deacetylase 1) to attenuate acetylation of p53.Intriguingly,Apak inhibits p53 activity by interacting with ATM (ataxia telangiectasia mutated),a previously identified p53 kinase and activator.In response to DNA damage,Apak is phosphorylated by ATM and dissociates from p53,resulting in p53 activation and apoptosis induction.These findings revealed Apak as a negative regulator of p53-mediated apoptosis and the dual role of ATM on p53 regulation.Finally,we recently identified more KRAB-type zinc-finger proteins which could selectively regulate p53-mediated transcription in an Apak-similar manner.We will present new progress from the studies and discuss the mechanistic and functional implications of KRAB-type zinc-finger proteins in p53regulation and cancer therapy.