Mre11-Rad50 oligomerization promotes DNA double-strand break repair

Vera M. Kissling, Giordano Reginato, Eliana Bianco, Kristina Kasaciunaite, Janny Tilma, Gea Cereghetti, Natalie Schindler, Sung Sik Lee, Raphaël Guérois, Brian Luke, Ralf Seidel, Petr Cejka () and Matthias Peter ()
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Vera M. Kissling: Eidgenössische Technische Hochschule (ETH)
Giordano Reginato: Eidgenössische Technische Hochschule (ETH)
Eliana Bianco: Eidgenössische Technische Hochschule (ETH)
Kristina Kasaciunaite: Universität Leipzig
Janny Tilma: Eidgenössische Technische Hochschule (ETH)
Gea Cereghetti: Eidgenössische Technische Hochschule (ETH)
Natalie Schindler: Johannes Gutenberg University
Sung Sik Lee: Eidgenössische Technische Hochschule (ETH)
Raphaël Guérois: CNRS, Université Paris-Sud, Université Paris-Saclay
Brian Luke: Johannes Gutenberg University
Ralf Seidel: Universität Leipzig
Petr Cejka: Eidgenössische Technische Hochschule (ETH)
Matthias Peter: Eidgenössische Technische Hochschule (ETH)

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The conserved Mre11-Rad50 complex is crucial for the detection, signaling, end tethering and processing of DNA double-strand breaks. While it is known that Mre11-Rad50 foci formation at DNA lesions accompanies repair, the underlying molecular assembly mechanisms and functional implications remained unclear. Combining pathway reconstitution in electron microscopy, biochemical assays and genetic studies, we show that S. cerevisiae Mre11-Rad50 with or without Xrs2 forms higher-order assemblies in solution and on DNA. Rad50 mediates such oligomerization, and mutations in a conserved Rad50 beta-sheet enhance or disrupt oligomerization. We demonstrate that Mre11-Rad50-Xrs2 oligomerization facilitates foci formation, DNA damage signaling, repair, and telomere maintenance in vivo. Mre11-Rad50 oligomerization does not affect its exonuclease activity but drives endonucleolytic cleavage at multiple sites on the 5′-DNA strand near double-strand breaks. Interestingly, mutations in the human RAD50 beta-sheet are linked to hereditary cancer predisposition and our findings might provide insights into their potential role in chemoresistance.

Date: 2022
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DOI: 10.1038/s41467-022-29841-0

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