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The Mre11/Rad50/Nbs1 protein complex plays central enzymatic and signaling roles in the DNA-damage response. Nuclease (Mre11) and scaffolding (Rad50) components of MRN have been extensively characterized, but the molecular basis of Nbs1 function has remained elusive. Here, we present a 2.3A crystal structure of the N-terminal region of fission yeast Nbs1, revealing an unusual but conserved architecture in which the FHA- and BRCT-repeat domains structurally coalesce. We demonstrate that diphosphorylated pSer-Asp-pThr-Asp motifs, recently identified as multicopy docking sites within Mdc1, are evolutionarily conserved Nbs1 binding targets. Furthermore, we show that similar phosphomotifs within Ctp1, the fission yeast ortholog of human CtIP, promote interactions with the Nbs1 FHA domain that are necessary for Ctp1-dependent resistance to DNA damage. Finally, we establish that human Nbs1 interactions with Mdc1 occur through both its FHA- and BRCT-repeat domains, suggesting how their structural and functional interdependence underpins Nbs1 adaptor functions in the DNA-damage response.

Original publication

DOI

10.1016/j.cell.2009.07.043

Type

Journal article

Journal

Cell

Publication Date

02/10/2009

Volume

139

Pages

100 - 111

Keywords

Amino Acid Sequence, Cell Cycle Proteins, Chromosomal Proteins, Non-Histone, Crystallography, X-Ray, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Nuclear Proteins, Phosphorylation, Protein Structure, Tertiary, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Alignment