Abstract
Werner syndrome (WS) is characterized by the early onset of symptoms of premature aging, cancer, and genomic instability. The molecular basis of the defects is not understood but presumably relates to the DNA helicase and exonuclease 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 reported physical interaction between WRN and the tumor suppressor p53 suggest that p53 and WRN functionally interact in a pathway necessary for the normal cellular response. In this study, we have demonstrated that p53 inhibits the exonuclease activity of the purified full-length recombinant WRN protein. p53 did not have an effect on a truncated amino-terminal WRN fragment that retains exonuclease activity but lacks the physical interaction domain for p53 located in the carboxyl terminus. Two naturally occurring p53 mutants found in human cancer displayed a reduced ability to inhibit WRN exonuclease activity. In cells arrested in S phase with hydroxyurea, WRN exits the 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.
Highlights
Genomic instability is prevalent in the hereditary disorder Werner syndrome (WS).1 WS is a premature aging dis
We have provided the first evidence of a direct biochemical functional interaction between the WRN protein and p53. p53 is able to effectively inhibit the 3Ј to 5Ј exonuclease activity of WRN. p53 fails to perturb the exonuclease activity of two bacterial exonucleases, suggesting a specific interaction between WRN and p53
These results indicate that the inhibition of WRN exonuclease activity does not require a vast excess of p53 and suggest an important biological mechanism to regulate the degradative capacity of WRN at recessed 3Ј ends
Summary
Genomic instability is prevalent in the hereditary disorder Werner syndrome (WS). WS is a premature aging dis-. A number of recent findings suggest that p53 and WRN proteins function together to maintain genomic stability: (a) p53-mediated apoptosis is attenuated in WS cells [18], (b) overexpression of WRN results in enhanced p53-dependent transcriptional activity [19], (c) Sp1-mediated transcription of the WRN gene is modulated by p53 [20], and (d) WRN knockout mice display accelerated mortality in a p53-null background [21]. Despite the strong evidence that WRN and p53 associate with each other, there has been no evidence for a functional biochemical interaction between WRN and p53. The p53-WRN physical interaction suggests that the phenotypes of cancer and genomic instability in WS may involve p53 modulation of WRN catalytic function. To investigate the relationship of p53 and WRN protein, we have analyzed whether the ATPase, helicase, and exonuclease activities of WRN are modulated by p53. Our results demonstrate that p53 exerts a strong inhibitory effect on the exonuclease activity of WRN. The regulation of WRN by p53 is relevant to the important roles of these proteins in the maintenance of genome stability
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