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Identification of a coiled coil in werner syndrome protein that facilitates multimerization and promotes exonuclease processivity

Academic Article
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Overview

authors

  • Perry, J. J. P.
  • Asaithamby, A.
  • Barnebey, A.
  • Kiamanesch, F.
  • Chen, D. J.
  • Han, S.
  • Tainer, John
  • Yannone, S. M.

publication date

  • 2010

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Werner syndrome (WS) is a rare progeroid disorder characterized by genomic instability, increased cancer incidence, and early onset of a variety of aging pathologies. WS is unique among early aging syndromes in that affected individuals are developmentally normal, and phenotypic onset is in early adulthood. The protein defective in WS (WRN) is a member of the large RecQ family of helicases but is unique among this family in having an exonuclease. RecQ helicases form multimers, but the mechanism and consequence of multimerization remain incompletely defined. Here, we identify a novel heptad repeat coiled coil region between the WRN nuclease and helicase domains that facilitates multimerization of WRN. We mapped a novel and unique DNA-dependent protein kinase phosphorylation site proximal to the WRN multimerization region. However, phosphorylation at this site affected neither exonuclease activity nor multimeric state. We found that WRN nuclease is stimulated by DNA-dependent protein kinase independently of kinase activity or WRN nuclease multimeric status. In addition, WRN nuclease multimerization significantly increased nuclease processivity. We found that the novel WRN coiled coil domain is necessary for multimerization of the nuclease domain and sufficient to multimerize with full-length WRN in human cells. Importantly, correct homomultimerization is required for WRN function in vivo as overexpression of this multimerization domain caused increased sensitivity to camptothecin and 4-nitroquinoline 1-oxide similar to that in cells lacking functional WRN protein.

subject areas

  • 4-Nitroquinoline-1-oxide
  • Blotting, Western
  • Camptothecin
  • Chromatography, Gel
  • DNA Damage
  • Exodeoxyribonucleases
  • Exonucleases
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Phosphorylation
  • Polymerase Chain Reaction
  • Protein Multimerization
  • Protein Structure, Tertiary
  • RecQ Helicases
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Identity

PubMed Central ID

  • PMC2919133

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M110.124941

PubMed ID

  • 20516064
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Additional Document Info

start page

  • 25699

end page

  • 25707

volume

  • 285

issue

  • 33

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