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

Abstract

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.

• Authors: R Scott Williams, Gerald E Dodson, Oliver Limbo, Yoshiki Yamada, Jessica S Williams, Grant Guenther, Scott Classen, J N Mark Glover, Hiroshi Iwasaki, Paul Russell, John A Tainer
• Journal: Cell (Cell) Vol. 139 Issue 1 Pg. 87-99 (Oct 02 2009) ISSN: 1097-4172 [Electronic] United States
• PMID: 19804755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cell Cycle Proteins
• Chromosomal Proteins, Non-Histone
• Ctp1 protein, S pombe
• DNA-Binding Proteins
• MRE11 protein, human
• NBN protein, human
• Nbs1 protein, S pombe
• Nuclear Proteins
• Schizosaccharomyces pombe Proteins
• MRE11 Homologue Protein
• Acid Anhydride Hydrolases
• Rad50 protein, human
• DNA Repair Enzymes

Topics

• Acid Anhydride Hydrolases
• Cell Cycle Proteins (chemistry, genetics, metabolism)
• Chromosomal Proteins, Non-Histone (chemistry, genetics, metabolism)
• Crystallography, X-Ray
• DNA Repair
• DNA Repair Enzymes (metabolism)
• DNA-Binding Proteins (chemistry, metabolism)
• Humans
• MRE11 Homologue Protein
• Models, Molecular
• Mutation
• Nuclear Proteins (chemistry, genetics, metabolism)
• Protein Structure, Tertiary
• Scattering, Small Angle
• Schizosaccharomyces (metabolism)
• Schizosaccharomyces pombe Proteins (chemistry, genetics, metabolism)