A Novel Human p53 Isoform Is an Essential Element of the ATR-Intra-S Phase Checkpoint

Summary The archetypal human tumor suppressor p53 is considered to have unique transactivation properties. The assumption is based on the fact that additionally identified human p53 isoforms lack transcriptional activity. However, we provide evidence for the existence of an alternatively spliced p53 isoform (Δp53) that exerts its transcriptional activity independent from p53. In contrast to p53, Δp53 transactivates the endogenous p21 and 14-3-3σ but not the mdm2 , bax , and PIG3 promoter. Cell cycle studies showed that Δp53 displays its differential transcriptional activity only in damaged S phase cells. Upon activation of the ATR-intra-S phase checkpoint, Δp53, but not p53, transactivates the Cdk inhibitor p21 . Induction of p21 results in downregulation of cyclin A-Cdk activity and accordingly attenuation of S phase progression. Data demonstrate that the Δp53-p21-cyclin A-Cdk pathway is crucial to facilitate uncoupling of repair and replication events, indicating that Δp53 is an essential element of the ATR-intra-S phase checkpoint.