Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular 
mechanism of scaffolding functions

Rotheneeder, Matthia; Stakyte, Kristina; van de Logt, Erik; Bartho, Joseph D.; Lammens, Katja; Fan, Yilan; Alt, Aaron; Kessler, Brigitte; Jung, Christophe; Roos, Wynand P.; Steigenberger, Barbara; Hopfner, Karl-Peter

doi:10.1016/j.molcel.2022.12.003

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Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular mechanism of scaffolding functions

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Steigenberger, Barbara
Scientific Service Groups, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Rotheneeder, M., Stakyte, K., van de Logt, E., Bartho, J. D., Lammens, K., Fan, Y., et al. (2023). Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular mechanism of scaffolding functions. Molecular Cell, 83(2), 167-185. doi:10.1016/j.molcel.2022.12.003.

Cite as: https://hdl.handle.net/21.11116/0000-000C-F80B-1

Abstract

The DNA double-strand break repair complex Mre11-Rad50-Nbs1 (MRN) detects and nucleolytically pro-cesses DNA ends, activates the ATM kinase, and tethers DNA at break sites. How MRN can act both as nuclease and scaffold protein is not well understood. The cryo-EM structure of MRN from Chaetomium ther-mophilum reveals a 2:2:1 complex with a single Nbs1 wrapping around the autoinhibited Mre11 nuclease dimer. MRN has two DNA-binding modes, one ATP-dependent mode for loading onto DNA ends and one ATP-independent mode through Mre11???s C terminus, suggesting how it may interact with DSBs and intact DNA. MRNs two 60-nm-long coiled-coil domains form a linear rod structure, the apex of which is assembled by the two joined zinc-hook motifs. Apices from two MRN complexes can further dimerize, forming 120-nm spanning MRN-MRN structures. Our results illustrate the architecture of MRN and suggest how it mechanis-tically integrates catalytic and tethering functions.