 The P53 signaling pathway is activated by DNA damaging agents, leading to either cell cycle checkpoint activation or apoptosis. However, recent evidence suggests that most human cell types respond to ionizing radiation by undergoing stress-induced premature senescence, CYPS, instead of apoptosis. The P21WAF1 protein has emerged as a key player in the P53 pathway, regulating P53 and its upstream kinase, controlling gene expression, suppressing apoptosis, and inducing CYPS. This review examines the dynamic behaviors of P53 and P21 in the DNA damage response and highlights the gain of function properties of cancer-associated P53 mutations. The article also discusses obstacles in cancer therapeutic strategies aimed at reactivating wild-type P53 function and suggests alternative approaches that target the apoptotic threshold in cancer cells with differing P53 status. This article was authored by Rasmik Mazayans, Bonnie and Ray, April Scott, and others. We are article.tv, links in the description below.