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Title: WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role

Abstract

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.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director, Office of Science. Office of Biological andEnvironmental Research. Life Sciences Division
OSTI Identifier:
891194
Report Number(s):
LBNL-53236
R&D Project: L0423; BnR: 600303000; TRN: US200621%%657
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Structural and Molecular Biology; Journal Volume: 13; Related Information: Journal Publication Date: 2006
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; 60 APPLIED LIFE SCIENCES; AGING; ANIMAL CELLS; BIOCHEMISTRY; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DNA; DNA HELICASES; FUNCTIONALS; INACTIVATION; MAINTENANCE; MUTATIONS; NUCLEASES; PROCESSING; SPECIFICITY

Citation Formats

Perry, J. Jefferson P., Yannone, Steven M., Holden, Lauren G., Hitomi, Chiharu, Asaithamby, Aroumougame, Han, Seungil, Cooper, PriscillaK., Chen, David J., and Tainer, John A.. WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role. United States: N. p., 2006. Web. doi:10.1038/nsmb1088.
Perry, J. Jefferson P., Yannone, Steven M., Holden, Lauren G., Hitomi, Chiharu, Asaithamby, Aroumougame, Han, Seungil, Cooper, PriscillaK., Chen, David J., & Tainer, John A.. WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role. United States. doi:10.1038/nsmb1088.
Perry, J. Jefferson P., Yannone, Steven M., Holden, Lauren G., Hitomi, Chiharu, Asaithamby, Aroumougame, Han, Seungil, Cooper, PriscillaK., Chen, David J., and Tainer, John A.. Wed . "WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role". United States. doi:10.1038/nsmb1088. https://www.osti.gov/servlets/purl/891194.
@article{osti_891194,
title = {WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role},
author = {Perry, J. Jefferson P. and Yannone, Steven M. and Holden, Lauren G. and Hitomi, Chiharu and Asaithamby, Aroumougame and Han, Seungil and Cooper, PriscillaK. and Chen, David J. and Tainer, John A.},
abstractNote = {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.},
doi = {10.1038/nsmb1088},
journal = {Nature Structural and Molecular Biology},
number = ,
volume = 13,
place = {United States},
year = {Wed Feb 15 00:00:00 EST 2006},
month = {Wed Feb 15 00:00:00 EST 2006}
}