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Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex

Academic Article
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Overview

authors

  • Hammel, M.
  • Yu, Y. P.
  • Mahaney, B. L.
  • Cai, B.
  • Ye, R. Q.
  • Phipps, B. M.
  • Rambo, R. P.
  • Hura, G. L.
  • Pelikan, M.
  • So, S.
  • Abolfath, R. M.
  • Chen, D. J.
  • Lees-Miller, S. P.
  • Tainer, John

publication date

  • January 2010

journal

  • Journal of Biological Chemistry  Journal

abstract

  • DNA double strand break (DSB) repair by non-homologous end joining (NHEJ) is initiated by DSB detection by Ku70/80 (Ku) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) recruitment, which promotes pathway progression through poorly defined mechanisms. Here, Ku and DNA-PKcs solution structures alone and in complex with DNA, defined by x-ray scattering, reveal major structural reorganizations that choreograph NHEJ initiation. The Ku80 C-terminal region forms a flexible arm that extends from the DNA-binding core to recruit and retain DNA-PKcs at DSBs. Furthermore, Ku- and DNA-promoted assembly of a DNA-PKcs dimer facilitates trans-autophosphorylation at the DSB. The resulting site-specific autophosphorylation induces a large conformational change that opens DNA-PKcs and promotes its release from DNA ends. These results show how protein and DNA interactions initiate large Ku and DNA-PKcs rearrangements to control DNA-PK biological functions as a macromolecular machine orchestrating assembly and disassembly of the initial NHEJ complex on DNA.

subject areas

  • Antigens, Nuclear
  • DNA
  • DNA Breaks, Double-Stranded
  • DNA-Binding Proteins
  • Humans
  • Protein Binding
  • Protein Structure, Tertiary
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Identity

PubMed Central ID

  • PMC2801267

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.065615

PubMed ID

  • 19893054
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Additional Document Info

start page

  • 1414

end page

  • 1423

volume

  • 285

issue

  • 2

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