Structure of Mre11–Nbs1 complex yields insights into ataxia-telangiectasia–like disease mutations and DNA damage signaling
Open Access
- 17 June 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Structural & Molecular Biology
- Vol. 19 (7), 693-700
- https://doi.org/10.1038/nsmb.2323
Abstract
The Mre11–Rad50–Nbs1 (MRN) complex plays a central role in DNA damage signaling. The crystal structures of the Schizosaccharomyces pombe Mre11 catalytic domain in its apo form and in complex with a fragment of Nbs1 are now reported. Along with functional analyses, the work provides insight into checkpoint signaling and ATM activation as well as a framework to understand disease-related mutations. The Mre11–Rad50–Nbs1 (MRN) complex tethers, processes and signals DNA double-strand breaks, promoting genomic stability. To understand the functional architecture of MRN, we determined the crystal structures of the Schizosaccharomyces pombe Mre11 dimeric catalytic domain alone and in complex with a fragment of Nbs1. Two Nbs1 subunits stretch around the outside of the nuclease domains of Mre11, with one subunit additionally bridging and locking the Mre11 dimer via a highly conserved asymmetrical binding motif. Our results show that Mre11 forms a flexible dimer and suggest that Nbs1 not only is a checkpoint adaptor but also functionally influences Mre11-Rad50. Clinical mutations in Mre11 are located along the Nbs1-interaction sites and weaken the Mre11-Nbs1 interaction. However, they differentially affect DNA repair and telomere maintenance in Saccharomyces cerevisiae, potentially providing insight into their different human disease pathologies.Keywords
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