| Literature DB >> 19804755 |
R Scott Williams1, 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.
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.Entities:
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Year: 2009 PMID： 19804755 PMCID： PMC2762657 DOI： 10.1016/j.cell.2009.07.033
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582