Structural mechanism of endonucleolytic processing of blocked DNA ends and hairpins by Mre11-Rad50

Fabian Gut, Lisa Käshammer, Katja Lammens, Joseph D. Bartho, Anna-Maria Buggusch, Erik van de Logt, Brigitte Kessler, Karl-Peter Hopfner (2022) Structural mechanism of endonucleolytic processing of blocked DNA ends and hairpins by Mre11-Rad50. Molecular Cell 82: 1-10.  https://doi.org/10.1016/j.molcel.2022.07.019

Summary cited directly from the article:

DNA double-strand breaks (DSBs) threaten genome stability and are linked to tumorigenesis in humans. Repair of DSBs requires the removal of attached proteins and hairpins through a poorly understood but physiologically critical endonuclease activity by the Mre11-Rad50 complex. Here, we report cryoelectron microscopy (cryo-EM) structures of the bacterial Mre11-Rad50 homolog SbcCD bound to a protein-blocked DNA end and a DNA hairpin. The structures reveal that Mre11-Rad50 bends internal DNA for endonucleolytic cleavage and show how internal DNA, DNA ends, and hairpins are processed through a similar ATP-regulated conformational state. Furthermore, Mre11-Rad50 is loaded onto blocked DNA ends with Mre11 pointing away from the block, explaining the distinct biochemistries of 30 / 50 exonucleolytic and endonucleolytic incision through the way Mre11-Rad50 interacts with diverse DNA ends. In summary, our results unify Mre11-Rad50’s enigmatic nuclease diversity within a single structural framework and reveal how blocked DNA ends and hairpins are processed.