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Structural and functional analysis of mre11-3

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Overview

authors

  • Arthur, L. M.
  • Gustausson, K.
  • Hopfner, K. P.
  • Carson, C. T.
  • Stracker, T. H.
  • Karcher, A.
  • Felton, D.
  • Weitzman, M. D.
  • Tainer, John
  • Carney, J. P.

publication date

  • March 2004

journal

  • Nucleic Acids Research  Journal

abstract

  • The Mre11, Rad50 and Nbs1 proteins make up the conserved multi-functional Mre11 (MRN) complex involved in multiple, critical DNA metabolic processes including double-strand break repair and telomere maintenance. The Mre11 protein is a nuclease with broad substrate recognition, but MRN-dependent processes requiring the nuclease activity are not clearly defined. Here, we report the functional and structural characterization of a nuclease-deficient Mre11 protein termed mre11-3. Importantly, the hmre11-3 protein has wild-type ability to bind DNA, Rad50 and Nbs1; however, nuclease activity was completely abrogated. When expressed in cell lines from patients with ataxia telangiectasia-like disorder (ATLD), hmre11-3 restored the formation of ionizing radiation-induced foci. Consistent with the biochemical results, the 2.3 A crystal structure of mre11-3 from Pyrococcus furiosus revealed an active site structure with a wild-type-like metal-binding environment. The structural analysis of the H85L mutation provides a detailed molecular basis for the ability of mre11-3 to bind but not hydrolyze DNA. Together, these results establish that the mre11-3 protein provides an excellent system for dissecting nuclease-dependent and independent functions of the Mre11 complex.

subject areas

  • Cell Cycle Proteins
  • Cell Line
  • DNA
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Exonucleases
  • Humans
  • Models, Molecular
  • Mutation
  • Nuclear Proteins
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Identity

PubMed Central ID

  • PMC390353

International Standard Serial Number (ISSN)

  • 0305-1048

Digital Object Identifier (DOI)

  • 10.1093/nar/gkh343

PubMed ID

  • 15047855
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Additional Document Info

start page

  • 1886

end page

  • 1893

volume

  • 32

issue

  • 6

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