ATR controls the p21(WAF1/Cip1) protein up-regulation and apoptosis in response to low UV fluences

The universal cyclin‐dependent kinase inhibitor p21^WAF1/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 p21^WAF1/Cip1 expression in response to UVC radiation. We have shown that p21^WAF1/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 p21^WAF1/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 p21^WAF1/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 p21^WAF1/Cip1 and inhibits apoptosis. © 2011 Wiley Periodicals, Inc.