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Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair.

The Nijmegen breakage syndrome 1 (Nbs1) subunit of the Mre11-Rad50-Nbs1 (MRN) complex protects genome integrity by coordinating double-strand break (DSB) repair and checkpoint signaling through undefined interactions with ATM, MDC1, and Sae2/Ctp1/CtIP. Here, fission yeast and human Nbs1 structures defined by X-ray crystallography and small angle X-ray scattering (SAXS) reveal Nbs1 cardinal features: fused, extended, FHA-BRCT(1)-BRCT(2) domains flexibly linked to C-terminal Mre11- and ATM-binding motifs. Genetic, biochemical, and structural analyses of an Nbs1-Ctp1 complex show Nbs1 recruits phosphorylated Ctp1 to DSBs via binding of the Nbs1 FHA domain to a Ctp1 pThr-Asp motif. Nbs1 structures further identify an extensive FHA-BRCT interface, a bipartite MDC1-binding scaffold, an extended conformational switch, and the molecular consequences associated with cancer predisposing Nijmegen breakage syndrome mutations. Tethering of Ctp1 to a flexible Nbs1 arm suggests a mechanism for restricting DNA end processing and homologous recombination activities of Sae2/Ctp1/CtIP to the immediate vicinity of DSBs.

Pubmed ID: 19804755

Authors

  • Williams RS
  • Dodson GE
  • Limbo O
  • Yamada Y
  • Williams JS
  • Guenther G
  • Classen S
  • Glover JN
  • Iwasaki H
  • Russell P
  • Tainer JA

Journal

Cell

Publication Data

October 2, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA117638
  • Agency: NCI NIH HHS, Id: CA77325
  • Agency: NCI NIH HHS, Id: CA92584
  • Agency: NCI NIH HHS, Id: P01 CA092584
  • Agency: NCI NIH HHS, Id: P01 CA092584-06
  • Agency: NCI NIH HHS, Id: P01 CA092584-069002
  • Agency: NCI NIH HHS, Id: P01 CA092584-07
  • Agency: NCI NIH HHS, Id: P01 CA092584-079002
  • Agency: NCI NIH HHS, Id: P01 CA092584-08
  • Agency: NCI NIH HHS, Id: P01 CA092584-089002
  • Agency: NCI NIH HHS, Id: R01 CA117638
  • Agency: NCI NIH HHS, Id: R01 CA117638-05

Mesh Terms

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Crystallography, X-Ray
  • DNA Repair
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Humans
  • Models, Molecular
  • Mutation
  • Nuclear Proteins
  • Protein Structure, Tertiary
  • Scattering, Small Angle
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins