p53 modulates the exonuclease activity of Werner syndrome protein

Werner syndrome (WS) is characterized by the early onset of symptoms of pre mature aging, cancer, and genomic instability. The molecular basis of the d efects is not understood but presumably relates to the DNA helicase and exo nuclease activities of the protein encoded by the WRN gene that is mutated in the disease. The attenuation of p53-mediated apoptosis in WS cells and r eported physical interaction between WRN and the tumor suppressor p53 sugge st that p53 and WRN functionally interact in a pathway necessary for the no rmal cellular response. In this study, we have demonstrated that p53 inhibi ts the exonuclease activity of the purified full-length recombinant WRN pro tein. p53 did not have an effect on a truncated amino-terminal WRN fragment that retains exonuclease activity but lacks the physical interaction domai n for p53 located in the carboxyl terminus. Two naturally occurring p53 mut ants found in human cancer displayed a reduced ability to inhibit WRN exonu clease activity. In cells arrested in S phase with hydroxyurea, WRN exits t he nucleolus and colocalizes with p53 in the nucleoplasm. The regulation of WRN function by p53 is likely to play an important role in the maintenance of genomic integrity and prevention of cancer and other clinical symptoms associated with WS.