Sae2 controls Mre11 endo- and exonuclease activities by different mechanisms

Tomoki Tamai, Giordano Reginato, Ryusei Ojiri, Issei Morita, Alexandra Avrutis, Petr Cejka (), Miki Shinohara () and Katsunori Sugimoto ()
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Tomoki Tamai: Kindai University
Giordano Reginato: Università della Svizzera italiana (USI)
Ryusei Ojiri: Kindai University
Issei Morita: Kindai University
Alexandra Avrutis: the State University of New Jersey
Petr Cejka: Università della Svizzera italiana (USI)
Miki Shinohara: Kindai University
Katsunori Sugimoto: the State University of New Jersey

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract DNA double-strand breaks (DSBs) must be repaired to ensure cell survival and genomic integrity. In yeast, the Mre11-Rad50-Xrs2 complex (MRX) collaborates with Sae2 to initiate DSB repair. Sae2 stimulates two MRX nuclease activities, endonuclease and 3’−5’ exonuclease. However, how Sae2 controls the two nuclease activities remains enigmatic. Using a combined genetic and biochemical approach, we identified a separation-of-function rad50 mutation, rad50-C47, that causes a defect in Sae2-dependent MRX 3’−5’ exonuclease activity, but not endonuclease activity. We found that both the endo- and 3’−5’ exonuclease activities are essential to release Spo11 from DNA ends, whereas only the endonuclease activity is required for hairpin removal. We also uncovered that MRX-Sae2 endonuclease introduces a cleavage at defined distances from the Spo11-blocked end with gradually decreasing efficiency. Our findings demonstrate that Sae2 stimulates the MRX endo- and exonuclease activities via Rad50 by different mechanisms, ensuring diverse actions of MRX-Sae2 nuclease at DNA ends.

Date: 2024
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DOI: 10.1038/s41467-024-51493-5

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