The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The Mre11-Rad50 (MR) complex is crucial for sensing and processing DNA double-strand breaks, which are highly genotoxic lesions implicated in cancer.
• MR can recognize and process DNA ends, even when they are blocked or misfolded, highlighting its importance in DNA repair.

Purpose of the Study:

• To elucidate the structural mechanism of the MR complex in sensing and processing DNA double-strand breaks.
• To analyze the ATP-dependent conformational changes that regulate MR complex activity.

Main Methods:

• Determined the crystal structure of the catalytic head of the Thermotoga maritima MR complex.
• Analyzed ATP-dependent conformational changes using structural and biochemical approaches.

Main Results:

• The MR complex adopts an open conformation with a central Mre11 nuclease dimer and peripheral Rad50 molecules, suitable for sensing obstructed DNA breaks.
• ATP binding induces conformational changes, rotating key domains and forming a clamp-like structure with enhanced DNA-binding activity.
• The Mre11 C-terminal domain's flexible attachment to the nuclease domain facilitates these large conformational changes.

Conclusions:

• The MR complex functions as an ATP-controlled, transient molecular clamp at DNA double-strand breaks.
• Structural insights reveal how ATP binding regulates MR's DNA-binding and processing activities, crucial for genome stability.