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Mre11-Rad50 oligomerization promotes DNA double-strand break repair

Vera M Kissling1, Giordano Reginato1,2, Eliana Bianco1

  • 1Department of Biology, Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH), 8093, Zürich, Switzerland.

Nature Communications
|May 2, 2022
PubMed

Insights

The Mre11-Rad50 complex forms higher-order assemblies crucial for DNA double-strand break repair. This oligomerization impacts DNA repair, signaling, and telomere maintenance, offering insights into cancer predisposition and chemoresistance.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • The Mre11-Rad50 complex is essential for DNA double-strand break (DSB) repair pathways.
  • Mechanisms of Mre11-Rad50 complex assembly and its functional significance in vivo were not fully understood.

Purpose of the Study:

  • To elucidate the molecular assembly mechanisms of the Mre11-Rad50 complex.
  • To investigate the functional implications of Mre11-Rad50 complex oligomerization in DNA repair and related processes.

Main Methods:

  • Pathway reconstitution using electron microscopy.
  • Biochemical assays to study complex formation and activity.
  • Genetic studies in Saccharomyces cerevisiae.

Main Results:

  • Mre11-Rad50, with or without Xrs2, forms higher-order assemblies in solution and on DNA.
  • Rad50 mediates oligomerization, with mutations in its beta-sheet affecting assembly.
  • Oligomerization enhances foci formation, DNA damage signaling, repair, and telomere maintenance.
  • Oligomerization drives endonucleolytic cleavage of the 5'-DNA strand at DSBs without affecting exonuclease activity.

Conclusions:

  • Mre11-Rad50 complex oligomerization is a key mechanism for its function in DNA double-strand break repair.
  • Findings provide insights into hereditary cancer predisposition and potential chemoresistance mechanisms linked to human RAD50 mutations.

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