WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role
Journal Article
·
· Nature Structural and Molecular Biology
WRN is unique among the five human RecQ DNA helicases by 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 two-metal-ion mediated nuclease mechanism. 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, with WRN-specific adaptations consistent with dsDNA specificity and functionally important conformational changes. These results indicate WRN-exo is a human DnaQ family member and support analogous proof-reading activities that are stimulated by Ku70/80 with implications for WRN functions in age related pathologies and maintenance of genomic integrity.
- Research Organization:
- Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
- Sponsoring Organization:
- USDOE Director, Office of Science. Office of Biological andEnvironmental Research. Life Sciences Division
- DOE Contract Number:
- AC02-05CH11231
- OSTI ID:
- 891194
- Report Number(s):
- LBNL--53236; BnR: 600303000
- Journal Information:
- Nature Structural and Molecular Biology, Journal Name: Nature Structural and Molecular Biology Vol. 13
- Country of Publication:
- United States
- Language:
- English
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