The universal cyclin-dependent kinase inhibitor p21WAF1/Cip1 promotes cell cycle arrest and inhibits apoptosis in response to UV-induced DNA damage. Since the protein kinase ATR plays a major role in the cellular response to these carcinogenic lesions, we investigated the possible role of ATR in the modulation of p21WAF1/Cip1 expression in response to UVC radiation. We have shown that p21WAF1/Cip1 is up-regulated in human fibroblast and epithelial cells, but only in response to low UV fluences and low passage cells. Importantly, this up-regulation is ATR-dependent. In fact, in ATR-deficient or caffeine-treated cells UV light rather down-regulated the p21WAF1/Cip1 protein through SKP2-dependent ubiquitination and degradation via the proteasomal pathway. Furthermore, we present evidence that ATR inhibits apoptosis in response to low fluences of UV light, through inhibiting the cleavage of caspase 3 and PARP as well as the repression of the proapoptotic proteins BAX and BAK. Interestingly, ATR is also required for the stability of the p21WAF1/Cip1 protein in absence of genotoxic stress. Together, these results indicate that during the cellular response to low UVC fluences the ATR protein kinase up-regulates p21WAF1/Cip1 and inhibits apoptosis. © 2011 Wiley Periodicals, Inc.