The Werner syndrome protein contributes to induction of p53 by DNA damage.
Mutations in the p53 tumor-suppressor gene promote increased genomic instability and cancer. Mutations in the WRN gene, encoding a DNA helicase, underlie the segmental progeroid Werner syndrome (WS). WS is also associated with increased genomic instability and elevated cancer risk. The p53 and WRN proteins can engage in direct protein-protein interactions. We report that excess WRN elicits increased cellular p53 levels and potentiates p53-mediated apoptosis. Importantly, cells derived from WS patients exhibit an attenuated and delayed induction of p53 by UV or by the topoisomerase I inhibitor camptothecin. These results suggest that WRN may participate in the activation of p53 in response to certain types of DNA damage. Furthermore, the failure to induce p53 effectively may contribute to enhanced genomic instability and elevated cancer risk in WS patients.
Blander
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G
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Zalle
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Leal
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Bar-Or
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Yu
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Oren
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D002478:Cells, Cultured; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D005786:Gene Expression Regulation; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014898:Werner Syndrome / Q000378:metabolism* / Q000473:pathology; D000071657:Werner Syndrome Helicase
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase