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

94 Citations (Scopus)

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

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Exonucleases
Molecular Structure
DNA
RecQ Helicases
Werner Syndrome
Ions
DNA Helicases
Premature Aging
Coordination Complexes
Catalytic Domain
Metals
Maintenance
Pathology
Mutation
Neoplasms

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. / Perry, J. Jefferson P; Yannone, Steven M.; Holden, Lauren G.; Hitomi, Chiharu; Asaithamby, Aroumougame; Han, Seungil; Cooper, Priscilla K.; Chen, David J.; Tainer, John A.

In: Nature Structural and Molecular Biology, Vol. 13, No. 5, 14.05.2006, p. 414-422.

Research output: Contribution to journalArticle

Perry, JJP, Yannone, SM, Holden, LG, Hitomi, C, Asaithamby, A, Han, S, Cooper, PK, Chen, DJ & Tainer, JA 2006, 'WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing', Nature Structural and Molecular Biology, vol. 13, no. 5, pp. 414-422. https://doi.org/10.1038/nsmb1088
Perry, J. Jefferson P ; Yannone, Steven M. ; Holden, Lauren G. ; Hitomi, Chiharu ; Asaithamby, Aroumougame ; Han, Seungil ; Cooper, Priscilla K. ; Chen, David J. ; Tainer, John A. / WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. In: Nature Structural and Molecular Biology. 2006 ; Vol. 13, No. 5. pp. 414-422.
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