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

Nature Structural & Molecular Biology
J Jefferson P PerryJohn A Tainer

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.

References

Apr 12, 1996·Science·C E YuG D Schellenberg
May 27, 1997·Proceedings of the National Academy of Sciences of the United States of America·A R MushegianE V Koonin
May 2, 1998·Science·M MelekD C van Gent
Oct 15, 1998·Nature Genetics·S HuangJ Campisi
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·K P HopfnerB Angerer
Jun 9, 1999·Current Biology : CB·J K KarowI D Hickson
Jun 16, 1999·Structure·S DoubliéT Ellenberger
Nov 5, 1999·Structure·G S Salvesen
Dec 22, 1999·Nucleic Acids Research·M J MoserR J Monnat
Jun 28, 2000·Nucleic Acids Research·S HuangJ Campisi
Jun 26, 2001·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·S SakamotoA Shimamoto
Jul 31, 2001·The Journal of Biological Chemistry·S M YannoneD J Chen
Sep 27, 2001·The Journal of Biological Chemistry·P L OpreskoV A Bohr
Aug 31, 2002·Nucleic Acids Research·Baomin Li, Lucio Comai
Sep 24, 2002·Journal of Cell Science·Cayetano von Kobbe, Vilhelm A Bohr
Mar 4, 2003·Nature Reviews. Cancer·Ian D Hickson
May 17, 2003·The Journal of Biological Chemistry·Kathy BayntonErling Seeberg
Oct 1, 2003·The EMBO Journal·Douglas A BernsteinJames L Keck
Oct 10, 2003·The Journal of Biological Chemistry·Cayetano von KobbeVilhelm A Bohr
Mar 18, 2004·The Journal of Biological Chemistry·Wen-Hsing ChengVilhelm A Bohr
Apr 2, 2004·Science of Aging Knowledge Environment : SAGE KE·Raymond J Monnat, Yannick Saintigny
Apr 16, 2004·DNA Repair·Cristina SwansonRaymond J Monnat
Jul 29, 2004·DNA Repair·David S ShinJohn A Tainer
Sep 1, 2004·Mechanisms of Ageing and Development·Lucio Comai, Baomin Li
Oct 19, 2004·The Journal of Biological Chemistry·Ashwini S Kamath-LoebLawrence A Loeb
Sep 6, 2005·Journal of Cell Science·Li LanAkira Yasui

❮ Previous
Next ❯

Citations

Jul 31, 2007·Cellular and Molecular Life Sciences : CMLS·L S Cox, R G A Faragher
Apr 16, 2013·DNA Repair·Takashi TadokoroVilhelm A Bohr
Sep 22, 2010·Quarterly Reviews of Biophysics·Wei Yang
Jun 19, 2008·Biochemistry·Rika KusumotoVilhelm A Bohr
Jul 12, 2013·Nature Reviews. Cancer·Robert M Brosh
Apr 15, 2008·Nature Structural & Molecular Biology·Elsa D GarcinJohn A Tainer
Aug 13, 2010·Metallomics : Integrated Biometal Science·Joseph E Deweese, Neil Osheroff
Jan 12, 2011·Proceedings of the National Academy of Sciences of the United States of America·Monika AggarwalRobert M Brosh
Aug 12, 2010·Antioxidants & Redox Signaling·Katherine S PawelczakJohn J Turchi
Aug 29, 2006·Nucleic Acids Research·Michael P Killoran, James L Keck
Nov 17, 2007·Nucleic Acids Research·Robert M Brosh, Vilhelm A Bohr
Jul 26, 2008·Nucleic Acids Research·Joseph E DeweeseNeil Osheroff
Jul 22, 2006·Annual Review of Genetics·Leonard Wu, Ian D Hickson
Mar 13, 2014·Annual Review of Biochemistry·Deborah L CroteauVilhelm A Bohr
Jun 20, 2014·Carcinogenesis·Raghavendra A ShamannaVilhelm A Bohr
Dec 2, 2009·HFSP Journal·Alessandro Vindigni, Ian D Hickson
Aug 30, 2014·Nucleic Acids Research·Jolanta CzerwińskaElżbieta Speina
Feb 15, 2011·Nature Chemical Biology·Yu-Yuan HsiaoHanna S Yuan
Apr 16, 2010·Biophysical Chemistry·Alessandro VindigniOpher Gileadi
Nov 17, 2009·Biochimica Et Biophysica Acta·J J P PerryJ A Tainer
Jun 26, 2007·Experimental Gerontology·Wen-Hsing ChengVilhelm A Bohr
Nov 23, 2006·Mechanisms of Ageing and Development·Rika KusumotoVilhelm A Bohr
Feb 24, 2016·Pharmacology & Therapeutics·Pounami SamadderLumir Krejci
May 10, 2015·DNA Repair·James M DaleyPatrick Sung
Dec 6, 2011·Current Opinion in Biotechnology·Steven M YannoneJohn A Tainer
Apr 1, 2014·DNA Repair·Gabrielle J GrundyStuart L Rulten
Apr 1, 2014·DNA Repair·Anthony J DavisDavid J Chen
Dec 3, 2014·Cell Reports·Fengtao SuAroumougame Asaithamby

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.