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Free keywords:
STRAND BREAK REPAIR; HOMOLOGY-DIRECTED REPAIR; DEPENDENT DNA-BINDING;
RAD50 ZINC-HOOK; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; NUCLEASE
COMPLEX; MRE11 NUCLEASE; ATM ACTIVATION; MRN COMPLEXBiochemistry & Molecular Biology; Cell Biology;
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.
