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ATMMACHINE Report Summary

Project ID: 322869
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - ATMMACHINE (Structural mechanism of recognition, signaling and resection of DNA double-strand breaks)

In this project, we study the structural mechanism how DNA double-strand breaks are detected, signaled and repaired. At the center of our investigations is the Mre11-Rad50-Nbs1 complex (MRN) that detects DNA ends, recruits and activates the DNA damage signaling kinase ATM, and prepares DNA ends for further repair by cleaning obstructed ends through an ATP dependent nuclease. Substantial progress has been made with respect to macromolecular interactions of the Mre11-Rad50-Nbs1 complex with DNA and other protein factors. We could reveal how Rad50 interacts with DNA and how ATP and DNA binding are allosterically coupled. Further results show that the ATP state of Rad50 is particularly important for ATM activation at telomeres, but also point towards an yet to be discovered functional state of the MRN complex in cleaving DNA. We furthermore contributed to identifying a role of MRN in cytosolic DNA sensing and sister-chromatid interactions. Our structural results provide a first general framework for the interaction of Rad50/SMC family ABC ATPases with DNA and help unify the chemo-mechanical mechanism of ABC proteins in evolution.

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