Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair

Area of Science:

• Molecular Biology
• DNA Repair Mechanisms
• Structural Biology

Background:

• The Mre11-Rad50-Nbs1 (MRN) complex is crucial for detecting DNA double-strand breaks (DSBs).
• MRN complex activates the ATM checkpoint kinase and initiates homologous recombination (HR) repair.
• Understanding Mre11's dual roles in DNA bridging and nucleolytic processing is key to DSB repair.

Purpose of the Study:

• To elucidate the structural and functional roles of Mre11 in initiating DSB repair.
• To investigate how Mre11 dimerization and endonuclease activity contribute to DNA repair pathways.
• To provide a molecular basis for understanding Mre11 mutations linked to ataxia telangiectasia-like disorder (ATLD).

Main Methods:

• Combined small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11.
• Utilized mutational analyses of fission yeast Mre11 to assess functional impacts.
• Investigated Mre11 dimer-DNA interactions and endonuclease activity.

Main Results:

• Mre11 dimer adopts a U-shaped structure essential for MRN complex assembly and DNA end binding.
• Mutations impairing Mre11 endonuclease activity compromise cell survival after DSB induction.
• Loss of endonuclease activity did not affect MRN assembly or Ctp1 recruitment to DSBs.

Conclusions:

• Mre11 dimerization and nuclease activities are critical for initiating DSB and collapsed replication fork repair.
• The study provides structural insights into Mre11's function in DNA repair.
• Findings offer a molecular foundation for understanding ATLD-associated Mre11 mutations.