Structure of Mre11–Nbs1 complex yields insights into ataxia-telangiectasia–like disease mutations and DNA damage signaling

• Published in: Nature structural & molecular biology Vol. 19; no. 7; pp. 693 - 700
• Main Authors: Schiller, Christian B, Lammens, Katja, Guerini, Ilaria, Coordes, Britta, Feldmann, Heidi, Schlauderer, Florian, Möckel, Carolin, Schele, Alexandra, Strässer, Katja, Jackson, Stephen P, Hopfner, Karl-Peter
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2012; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/337/1427/2122; 631/45/535; Binding Sites; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Chromosomal Proteins, Non-Histone - chemistry; Chromosomal Proteins, Non-Histone - metabolism; Deoxyribonucleic acid; Dimerization; Disease; DNA; DNA Damage; Genetic aspects; Humans; Life Sciences; Membrane Biology; Models, Molecular; Molecular structure; Mutation; Protein Conformation; Protein Structure; Protein-protein interactions; Saccharomyces; Saccharomyces cerevisiae; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins - chemistry; Schizosaccharomyces pombe Proteins - metabolism; Signal Transduction; United Kingdom; Germany
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2323

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.