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

Cell | Oct 2, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19804755

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 RIS Download

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

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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

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