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

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 ((delta)p53) that exerts its transcriptional activity independent from p53. In contrast to p53, (delta)p53 transactivates the endogenous p21 and 14-3-3(sigma) but not the mdm2, bax, and PIG3 promoter. Cell cycle studies showed that (delta)p53 displays its differential transcriptional activity only in damaged S phase cells. Upon activation of the ATR-intra-S phase checkpoint, (delta)p53, 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 (delta)p53-p21-cyclin A-Cdk pathway is crucial to facilitate uncoupling of repair and replication events, indicating that (delta)p53 is an essential element of the ATR-intra-S phase checkpoint.