WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing

J. Jefferson P Perry, Steven M. Yannone, Lauren G. Holden, Chiharu Hitomi, Aroumougame Asaithamby, Seungil Han, Priscilla K. Cooper, David J. Chen, John A. Tainer

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

WRN is unique among the five human RecQ DNA helicases in having a functional exonuclease domain (WRN-exo) and being defective in the premature aging and cancer-related disorder Werner syndrome. Here, we characterize WRN-exo crystal structures, biochemical activity and participation in DNA end joining. Metal-ion complex structures, active site mutations and activity assays reveal a nuclease mechanism mediated by two metal ions. The DNA end-binding Ku70/80 complex specifically stimulates WRN-exo activity, and structure-based mutational inactivation of WRN-exo alters DNA end joining in human cells. We furthermore establish structural and biochemical similarities of WRN-exo to DnaQ-family replicative proofreading exonucleases, describing WRN-specific adaptations consistent with double-stranded DNA specificity and functionally important conformational changes. These results indicate WRN-exo is a human DnaQ family member and support DnaQ-like proofreading activities stimulated by Ku70/80, with implications for WRN functions in age-related pathologies and maintenance of genomic integrity.

Original languageEnglish (US)
Pages (from-to)414-422
Number of pages9
JournalNature Structural and Molecular Biology
Volume13
Issue number5
DOIs
StatePublished - May 14 2006

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Perry, J. J. P., Yannone, S. M., Holden, L. G., Hitomi, C., Asaithamby, A., Han, S., Cooper, P. K., Chen, D. J., & Tainer, J. A. (2006). WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. Nature Structural and Molecular Biology, 13(5), 414-422. https://doi.org/10.1038/nsmb1088