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Mol Cell. 2019 Aug 26. pii: S1097-2765(19)30590-8. doi: 10.1016/j.molcel.2019.07.035. [Epub ahead of print]

Mechanism of DNA End Sensing and Processing by the Mre11-Rad50 Complex.

Author information

1
Department of Biochemistry, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Gene Center, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
2
Department of Biochemistry, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Gene Center, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Center for Integrated Protein Science, 81377 Munich, Germany. Electronic address: hopfner@genzentrum.lmu.de.

Abstract

DNA double-strand breaks (DSBs) threaten genome stability throughout life and are linked to tumorigenesis in humans. To initiate DSB repair by end joining or homologous recombination, the Mre11-nuclease Rad50-ATPase complex detects and processes diverse and obstructed DNA ends, but a structural mechanism is still lacking. Here we report cryo-EM structures of the E. coli Mre11-Rad50 homolog SbcCD in resting and DNA-bound cutting states. In the resting state, Mre11's nuclease is blocked by ATP-Rad50, and the Rad50 coiled coils appear flexible. Upon DNA binding, the two coiled coils zip up into a rod and, together with the Rad50 nucleotide-binding domains, form a clamp around dsDNA. Mre11 moves to the side of Rad50, binds the DNA end, and assembles a DNA cutting channel for the nuclease reactions. The structures reveal how Mre11-Rad50 can detect and process diverse DNA ends and uncover a clamping and gating function for the coiled coils.

KEYWORDS:

ABC ATPase; DNA double-strand breaks; DNA repair; Mre11-Rad50 complex; SMC-like proteins; SbcC-SbcD complex; coiled-coil; cryoelectron microscopy; homologous recombination; nuclease

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